Recent Journal Articles: Neuroscience -- Neurotransmitter.net

Recent Articles in Annual Review of Neuroscience

Gold JI, Shadlen MN
The neural basis of decision making.
Annu Rev Neurosci. 2007;30535-74.
The study of decision making spans such varied fields as neuroscience, psychology, economics, statistics, political science, and computer science. Despite this diversity of applications, most decisions share common elements including deliberation and commitment. Here we evaluate recent progress in understanding how these basic elements of decision formation are implemented in the brain. We focus on simple decisions that can be studied in the laboratory but emphasize general principles likely to extend to other settings. [Abstract]

Schlaggar BL, McCandliss BD
Development of neural systems for reading.
Annu Rev Neurosci. 2007;30475-503.
Functional and structural neuroimaging studies of adult readers have provided a deeper understanding of the neural basis of reading, yet such findings also elicit new questions about how developing neural systems come to support this learned ability. A developmental cognitive neuroscience approach provides insights into how skilled reading emerges in the developing brain, yet also raises new methodological challenges. This review focuses on functional changes that occur during reading acquisition in cortical regions associated with both the perception of visual words and spoken language, and it examines how such functional changes differ within developmental reading disabilities. We integrate these findings within an interactive specialization framework of functional development and propose that such a framework may provide insights into how individual differences at several levels of observation (genetics, white matter tract structure, functional organization of language, cultural organization of writing systems) impact the emergence of neural systems involved in reading ability and disability. [Abstract]

Shapiro L, Love J, Colman DR
Adhesion molecules in the nervous system: structural insights into function and diversity.
Annu Rev Neurosci. 2007;30451-74.
The unparalleled complexity of intercellular connections in the nervous system presents requirements for high levels of both specificity and diversity for the proteins that mediate cell adhesion. Here we describe recent advances toward understanding the molecular mechanisms that underlie adhesive binding, specificity, and diversity for several well-characterized families of adhesion molecules in the nervous system. Although many families of adhesion proteins, including cadherins and immunoglobulin superfamily members, are utilized in neural and nonneural contexts, nervous system-specific diversification mechanisms, such as precisely regulated alternative splicing, provide an important means to enable their function in the complex context of the nervous system. [Abstract]

Schultz W
Multiple dopamine functions at different time courses.
Annu Rev Neurosci. 2007;30259-88.
Many lesion studies report an amazing variety of deficits in behavioral functions that cannot possibly be encoded in great detail by the relatively small number of midbrain dopamine neurons. Although hoping to unravel a single dopamine function underlying these phenomena, electrophysiological and neurochemical studies still give a confusing, mutually exclusive, and partly contradictory account of dopamine's role in behavior. However, the speed of observed phasic dopamine changes varies several thousand fold, which offers a means to differentiate the behavioral relationships according to their time courses. Thus dopamine is involved in mediating the reactivity of the organism to the environment at different time scales, from fast impulse responses related to reward via slower changes with uncertainty, punishment, and possibly movement to the tonic enabling of postsynaptic motor, cognitive, and motivational systems deficient in Parkinson's disease. [Abstract]

Gao Q, Horvath TL
Neurobiology of feeding and energy expenditure.
Annu Rev Neurosci. 2007;30367-98.
Significant advancements have been made in the past century regarding the neuronal control of feeding behavior and energy expenditure. The effects and mechanisms of action of various peripheral metabolic signals on the brain have become clearer. Molecular and genetic tools for visualizing and manipulating individual components of brain homeostatic systems in combination with neuroanatomical, electrophysiological, behavioral, and pharmacological techniques have begun to elucidate the molecular and neuronal mechanisms of complex feeding behavior and energy expenditure. This review highlights some of these advancements that have led to the current understanding of the brain's involvement in the acute and chronic regulation of energy homeostasis. [Abstract]

Vargas ME, Barres BA
Why is Wallerian degeneration in the CNS so slow?
Annu Rev Neurosci. 2007;30153-79.
Wallerian degeneration (WD) is the set of molecular and cellular events by which degenerating axons and myelin are cleared after injury. Why WD is rapid and robust in the PNS but slow and incomplete in the CNS is a longstanding mystery. Here we review current work on the mechanisms of WD with an emphasis on deciphering this mystery and on understanding whether slow WD in the CNS could account for the failure of CNS axons to regenerate. [Abstract]

Vosshall LB, Stocker RF
Molecular architecture of smell and taste in Drosophila.
Annu Rev Neurosci. 2007;30505-33.
The chemical senses-smell and taste-allow animals to evaluate and distinguish valuable food resources from dangerous substances in the environment. The central mechanisms by which the brain recognizes and discriminates attractive and repulsive odorants and tastants, and makes behavioral decisions accordingly, are not well understood in any organism. Recent molecular and neuroanatomical advances in Drosophila have produced a nearly complete picture of the peripheral neuroanatomy and function of smell and taste in this insect. Neurophysiological experiments have begun to provide insight into the mechanisms by which these animals process chemosensory cues. Given the considerable anatomical and functional homology in smell and taste pathways in all higher animals, experimental approaches in Drosophila will likely provide broad insights into the problem of sensory coding. Here we provide a critical review of the recent literature in this field and comment on likely future directions. [Abstract]

Banerjee S, Bhat MA
Neuron-glial interactions in blood-brain barrier formation.
Annu Rev Neurosci. 2007;30235-58.
The blood brain barrier (BBB) evolved to preserve the microenvironment of the highly excitable neuronal cells to allow for action potential generation and propagation. Intricate molecular interactions between two main cell types, the neurons and the glial cells, form the underlying basis of the critical functioning of the nervous system across species. In invertebrates, interactions between neurons and glial cells are central in establishing a functional BBB. However, in vertebrates, the BBB formation and function is coordinated by interactions between neurons, glial cells, and endothelial cells. Here we review the neuron-glial interaction-based blood barriers in invertebrates and vertebrates and provide an evolutionary perspective as to how a glial-barrier system in invertebrates evolved into an endothelial barrier system. We also summarize the clinical relevance of the BBB as this protective barrier becomes disadvantageous in the pharmacological treatment of various neurological disorders. [Abstract]

Vollrath MA, Kwan KY, Corey DP
The micromachinery of mechanotransduction in hair cells.
Annu Rev Neurosci. 2007;30339-65.
Mechanical stimuli generated by head movements and changes in sound pressure are detected by hair cells with amazing speed and sensitivity. The mechanosensitive organelle, the hair bundle, is a highly elaborated structure of actin-based stereocilia arranged in precise rows of increasing height. Extracellular linkages contribute to its cohesion and convey forces to mechanically gated channels. Channel opening is nearly instantaneous and is followed by a process of sensory adaptation that keeps the channels poised in their most sensitive range. This process is served by motors, scaffolds, and homeostatic mechanisms. The molecular constituents of this process are rapidly being elucidated, especially by the discovery of deafness genes and antibody targets. [Abstract]

McAllister AK
Dynamic aspects of CNS synapse formation.
Annu Rev Neurosci. 2007;30425-50.
The mammalian central nervous system (CNS) requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between thousands of differentiating neurons. Proper synapse formation during childhood provides the substrate for cognition, whereas improper formation or function of these synapses leads to neurodevelopmental disorders, including mental retardation and autism. Recent work has begun to identify some of the early cellular events in synapse formation as well as the molecular signals that initiate this process. However, despite the wealth of information published on this topic in the past few years, some of the most fundamental questions about how, whether, and where glutamatergic synapses form in the mammalian CNS remain unanswered. This review focuses on the dynamic aspects of the early cellular and molecular events in the initial assembly of glutamatergic synapses in the mammalian CNS. [Abstract]

Eichenbaum H, Yonelinas AP, Ranganath C
The medial temporal lobe and recognition memory.
Annu Rev Neurosci. 2007;30123-52.
The ability to recognize a previously experienced stimulus is supported by two processes: recollection of the stimulus in the context of other information associated with the experience, and a sense of familiarity with the features of the stimulus. Although familiarity and recollection are functionally distinct, there is considerable debate about how these kinds of memory are supported by regions in the medial temporal lobes (MTL). Here, we review evidence for the distinction between recollection and familiarity and then consider the evidence regarding the neural mechanisms of these processes. Evidence from neuropsychological, neuroimaging, and neurophysiological studies of humans, monkeys, and rats indicates that different subregions of the MTL make distinct contributions to recollection and familiarity. The data suggest that the hippocampus is critical for recollection but not familiarity. The parahippocampal cortex also contributes to recollection, possibly via the representation and retrieval of contextual (especially spatial) information, whereas perirhinal cortex contributes to and is necessary for familiarity-based recognition. The findings are consistent with an anatomically guided hypothesis about the functional organization of the MTL and suggest mechanisms by which the anatomical components of the MTL interact to support the phenomenology of recollection and familiarity. [Abstract]

Murray EA, Bussey TJ, Saksida LM
Visual perception and memory: a new view of medial temporal lobe function in primates and rodents.
Annu Rev Neurosci. 2007;3099-122.
The prevailing view of medial temporal lobe (MTL) function has two principal elements: first, that the MTL subserves memory but not perception, and second, that the many anatomically distinctive parts of the MTL function together in the service of declarative memory. Recent neuropsychological studies have, however, challenged both opinions. First, studies in rodents, nonhuman primates, and humans suggest that the perirhinal cortex represents information about objects for both mnemonic and perceptual purposes. Second, the idea that MTL components contribute to declarative memory in similar ways has also been contradicted. Whereas the perirhinal cortex plays an essential role in familiarity-based object recognition, the hippocampus contributes little, if at all, to this function. In both primates and rodents, the hippocampus contributes to the memory and perception of places and paths, whereas the perirhinal cortex does so for objects and the contents of scenes. [Abstract]

Orr HT, Zoghbi HY
Trinucleotide repeat disorders.
Annu Rev Neurosci. 2007;30575-621.
The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets. [Abstract]

Wallis JD
Orbitofrontal cortex and its contribution to decision-making.
Annu Rev Neurosci. 2007;3031-56.
Damage to orbitofrontal cortex (OFC) produces an unusual pattern of deficits. Patients have intact cognitive abilities but are impaired in making everyday decisions. Here we review anatomical, neuropsychological, and neurophysiological evidence to determine the neuronal mechanisms that might underlie these impairments. We suggest that OFC plays a key role in processing reward: It integrates multiple sources of information regarding the reward outcome to derive a value signal. In effect, OFC calculates how rewarding a reward is. This value signal can then be held in working memory where it can be used by lateral prefrontal cortex to plan and organize behavior toward obtaining the outcome, and by medial prefrontal cortex to evaluate the overall action in terms of its success and the effort that was required. Thus, acting together, these prefrontal areas can ensure that our behavior is most efficiently directed towards satisfying our needs. [Abstract]

Knudsen EI
Fundamental components of attention.
Annu Rev Neurosci. 2007;3057-78.
A mechanistic understanding of attention is necessary for the elucidation of the neurobiological basis of conscious experience. This chapter presents a framework for thinking about attention that facilitates the analysis of this cognitive process in terms of underlying neural mechanisms. Four processes are fundamental to attention: working memory, top-down sensitivity control, competitive selection, and automatic bottom-up filtering for salient stimuli. Each process makes a distinct and essential contribution to attention. Voluntary control of attention involves the first three processes (working memory, top-down sensitivity control, and competitive selection) operating in a recurrent loop. Recent results from neurobiological research on attention are discussed within this framework. [Abstract]

Parrish JZ, Emoto K, Kim MD, Jan YN
Mechanisms that regulate establishment, maintenance, and remodeling of dendritic fields.
Annu Rev Neurosci. 2007;30399-423.
Although dendrite arborization patterns are hallmarks of neuronal type and critical determinants of neuronal function, how dendritic arbors take shape is still largely unknown. Transcription factors play important roles in specifying neuronal types and have a profound influence on dendritic arbor size and complexity. The space that a dendritic arbor occupies is determined largely by a combination of growth-promoting signals that regulate arbor size, chemotropic cues that steer dendrites into the appropriate space, and neurite-neurite contacts that ensure proper representation of the dendritic field and appropriate synaptic contacts. Dendritic arbors are largely maintained over the neuron's lifetime, but in some cases, dendritic arbors are refined, in large part as a result of neuronal activity. In this review, we summarize our current understanding of the cellular and molecular mechanisms that regulate dendritic field formation and influence the shaping of dendritic arbors. [Abstract]

Fields HL, Hjelmstad GO, Margolis EB, Nicola SM
Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement.
Annu Rev Neurosci. 2007;30289-316.
Ventral tegmental area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection target of VTA neurons recorded in vivo will be critical for determining their contribution to learned appetitive behaviors. [Abstract]

Madsen E, Gitlin JD
Copper and iron disorders of the brain.
Annu Rev Neurosci. 2007;30317-37.
Copper and iron are transition elements essential for life. These metals are required to maintain the brain's biochemistry such that deficiency or excess of either copper or iron results in central nervous system disease. This review focuses on the inherited disorders in humans that directly affect copper or iron homeostasis in the brain. Elucidation of the molecular genetic basis of these rare disorders has provided insight into the mechanisms of copper and iron acquisition, trafficking, storage, and excretion in the brain. This knowledge permits a greater understanding of copper and iron roles in neurobiology and neurologic disease and may allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis. [Abstract]

Chen ZL, Yu WM, Strickland S
Peripheral regeneration.
Annu Rev Neurosci. 2007;30209-33.
Whereas the central nervous system (CNS) usually cannot regenerate, peripheral nerves regenerate spontaneously after injury because of a permissive environment and activation of the intrinsic growth capacity of neurons. Functional regeneration requires axon regrowth and remyelination of the regenerated axons by Schwann cells. Multiple factors including neurotrophic factors, extracellular matrix (ECM) proteins, and hormones participate in Schwann cell dedifferentiation, proliferation, and remyelination. We describe the current understanding of peripheral axon regeneration and focus on the molecules and potential mechanisms involved in remyelination. [Abstract]

Taube JS
The head direction signal: origins and sensory-motor integration.
Annu Rev Neurosci. 2007;30181-207.
Navigation first requires accurate perception of one's spatial orientation within the environment, which consists of knowledge about location and directional heading. Cells within several limbic system areas of the mammalian brain discharge allocentrically as a function of the animal's directional heading, independent of the animal's location and ongoing behavior. These cells are referred to as head direction (HD) cells and are believed to encode the animal's perceived directional heading with respect to its environment. Although HD cells are found in several areas, the principal circuit for generating this signal originates in the dorsal tegmental nucleus and projects serially, with some reciprocal connections, to the lateral mammillary nucleus --> anterodorsal thalamus --> PoS, and terminates in the entorhinal cortex. HD cells receive multimodal information about landmarks and self-generated movements. Vestibular information appears critical for generating the directional signal, but motor/proprioceptive and landmark information are important for updating it. [Abstract]

Field GD, Chichilnisky EJ
Information processing in the primate retina: circuitry and coding.
Annu Rev Neurosci. 2007;301-30.
The function of any neural circuit is governed by connectivity of neurons in the circuit and the computations performed by the neurons. Recent research on retinal function has substantially advanced understanding in both areas. First, visual information is transmitted to the brain by at least 17 distinct retinal ganglion cell types defined by characteristic morphology, light response properties, and central projections. These findings provide a much more accurate view of the parallel visual pathways emanating from the retina than do previous models, and they highlight the importance of identifying distinct cell types and their connectivity in other neural circuits. Second, encoding of visual information involves significant temporal structure and interactions in the spike trains of retinal neurons. The functional importance of this structure is revealed by computational analysis of encoding and decoding, an approach that may be applicable to understanding the function of other neural circuits. [Abstract]

Alvarez VA, Sabatini BL
Anatomical and physiological plasticity of dendritic spines.
Annu Rev Neurosci. 2007;3079-97.
In excitatory neurons, most glutamatergic synapses are made on the heads of dendritic spines, each of which houses the postsynaptic terminal of a single glutamatergic synapse. We review recent studies demonstrating in vivo that spines are motile and plastic structures whose morphology and lifespan are influenced, even in adult animals, by changes in sensory input. However, most spines that appear in adult animals are transient, and the addition of stable spines and synapses is rare. In vitro studies have shown that patterns of neuronal activity known to induce synaptic plasticity can also trigger changes in spine morphology. Therefore, it is tempting to speculate that the plastic changes of spine morphology reflect the dynamic state of its associated synapse and are responsible to some extent for neuronal circuitry remodeling. Nevertheless, morphological changes are not required for all forms of synaptic plasticity, and whether changes in the spine shape and size significantly impact synaptic signals is unclear. [Abstract]

Hyman SE, Malenka RC, Nestler EJ
Neural mechanisms of addiction: the role of reward-related learning and memory.
Annu Rev Neurosci. 2006;29565-98.
Addiction is a state of compulsive drug use; despite treatment and other attempts to control drug taking, addiction tends to persist. Clinical and laboratory observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. The major substrates of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (involving the ventral and dorsal striatum and prefrontal cortex) that receive input from midbrain dopamine neurons. Here we review progress in identifying candidate mechanisms of addiction. [Abstract]

Dellovade T, Romer JT, Curran T, Rubin LL
The hedgehog pathway and neurological disorders.
Annu Rev Neurosci. 2006;29539-63.
The hedgehog pathway is a major regulator of embryonic development, and mutations that decrease its activity are known to be associated with severe defects in nervous system development. Recent evidence suggests hedgehog continues to function in adult tissue, normal as well as diseased, by regulating both cell proliferation and the production of growth and angiogenic factors. In the adult nervous system, this dual ability is especially important in regulating the behavior of neural stem and progenitor cells. This review summarizes information connecting hedgehog signaling and neural diseases, including neurodegenerative disorders and brain tumors, particularly medulloblastoma. We also describe the discovery and utility of small molecule agonists and antagonists of this pathway and their potential as novel types of therapeutics. [Abstract]

Pezet S, McMahon SB
Neurotrophins: mediators and modulators of pain.
Annu Rev Neurosci. 2006;29507-38.
The neurotrophin family of neurotrophic factors are well-known for their effects on neuronal survival and growth. Over the past decade, considerable evidence has accumulated from both humans and animals that one neurotrophin, nerve growth factor (NGF), is a peripheral pain mediator, particularly in inflammatory pain states. NGF is upregulated in a wide variety of inflammatory conditions, and NGF-neutralizing molecules are effective analgesic agents in many models of persistent pain. Such molecules are now being evaluated in clinical trials. NGF regulates the expression of a second neurotrophin, brain-derived neurotrophic factor (BDNF), in nociceptors. BDNF is released when nociceptors are activated, and it acts as a central modulator of pain. The chapter reviews the evidence for these roles (and briefly the effects of other neurotrophins), the range of conditions under which they act, and their mechanism of action. [Abstract]

Wu MC, David SV, Gallant JL
Complete functional characterization of sensory neurons by system identification.
Annu Rev Neurosci. 2006;29477-505.
System identification is a growing approach to sensory neurophysiology that facilitates the development of quantitative functional models of sensory processing. This approach provides a clear set of guidelines for combining experimental data with other knowledge about sensory function to obtain a description that optimally predicts the way that neurons process sensory information. This prediction paradigm provides an objective method for evaluating and comparing computational models. In this chapter we review many of the system identification algorithms that have been used in sensory neurophysiology, and we show how they can be viewed as variants of a single statistical inference problem. We then review many of the practical issues that arise when applying these methods to neurophysiological experiments: stimulus selection, behavioral control, model visualization, and validation. Finally we discuss several problems to which system identification has been applied recently, including one important long-term goal of sensory neuroscience: developing models of sensory systems that accurately predict neuronal responses under completely natural conditions. [Abstract]

Raichle ME, Mintun MA
Brain work and brain imaging.
Annu Rev Neurosci. 2006;29449-76.
Functional brain imaging with positron emission tomography and magnetic resonance imaging has been used extensively to map regional changes in brain activity. The signal used by both techniques is based on changes in local circulation and metabolism (brain work). Our understanding of the cell biology of these changes has progressed greatly in the past decade. New insights have emerged on the role of astrocytes in signal transduction as has an appreciation of the unique contribution of aerobic glycolysis to brain energy metabolism. Likewise our understanding of the neurophysiologic processes responsible for imaging signals has progressed from an assumption that spiking activity (output) of neurons is most relevant to one focused on their input. Finally, neuroimaging, with its unique metabolic perspective, has alerted us to the ongoing and costly intrinsic activity within brain systems that most likely represents the largest fraction of the brain's functional activity. [Abstract]

Montague PR, King-Casas B, Cohen JD
Imaging valuation models in human choice.
Annu Rev Neurosci. 2006;29417-48.
To make a decision, a system must assign value to each of its available choices. In the human brain, one approach to studying valuation has used rewarding stimuli to map out brain responses by varying the dimension or importance of the rewards. However, theoretical models have taught us that value computations are complex, and so reward probes alone can give only partial information about neural responses related to valuation. In recent years, computationally principled models of value learning have been used in conjunction with noninvasive neuroimaging to tease out neural valuation responses related to reward-learning and decision-making. We restrict our review to the role of these models in a new generation of experiments that seeks to build on a now-large body of diverse reward-related brain responses. We show that the models and the measurements based on them point the way forward in two important directions: the valuation of time and the valuation of fictive experience. [Abstract]

Cannon SC
Pathomechanisms in channelopathies of skeletal muscle and brain.
Annu Rev Neurosci. 2006;29387-415.
Ion channelopathies are a diverse array of human disorders caused by mutations in ion channel genes. This review focuses on the pathogenic mechanisms of channelopathies affecting skeletal muscle and brain arising from mutations of voltage-gated ion channels and fast ligand-gated ion channels expressed at the surface membrane. Derangements in channel function alter the electrical excitability of the cell and thereby increase susceptibility to transient symptomatic attacks including myasthenia, periodic paralysis, myotonic stiffness, seizures, headache, dyskinesia, or episodic ataxia. Although these disorders are rare, they stand out as exemplary cases for which disease pathogenesis can be traced from a point mutation to altered protein function, to altered cellular activity, and to clinical phenotype. The study of these disorders has provided insights on channel structure-function relations, the physiological roles of ion channels, and rational approaches toward therapeutic intervention for many disorders of cellular excitability. [Abstract]

Montcouquiol M, Crenshaw EB, Kelley MW
Noncanonical Wnt signaling and neural polarity.
Annu Rev Neurosci. 2006;29363-86.
The Wnt signaling pathway regulates multiple events in development and disease in both vertebrates and invertebrates. Recently, the noncanonical Wnt signaling cascades, those that do not signal through beta-catenin, have gained prominence for their role in the regulation of cellular polarity. It is not surprising that cellular polarization influences a number of different developmental events within the nervous system, including neurulation and neural tube closure, cellular migration, and uniform orientation of cells within an epithelial plane (planar cell polarity). In this review, we describe the differences between the canonical and noncanonical pathways, summarize recent data illustrating the roles of the noncanonical Wnt pathway in different polarizing events during neural development, and discuss the potential molecular mechanisms that underlie the generation of cellular asymmetry and polarity. [Abstract]

Recent Articles in Nature Reviews Neuroscience

Rutishauser U
Polysialic acid in the plasticity of the developing and adult vertebrate nervous system.
Nat Rev Neurosci. 2007 Dec 5;
Polysialic acid (PSA) is a cell-surface glycan with an enormous hydrated volume that serves to modulate the distance between cells. This regulation has direct effects on several cellular mechanisms that underlie the formation of the vertebrate nervous system, most conspicuously in the migration and differentiation of progenitor cells and the growth and targeting of axons. PSA is also involved in a number of plasticity-related responses in the adult CNS, including changes in circadian and hormonal patterns, adaptations to pain and stress, and aspects of learning and memory. The ability of PSA to increase the plasticity of neural cells is being exploited to improve the repair of adult CNS tissue. [Abstract]

Patterson K, Nestor PJ, Rogers TT
Where do you know what you know? The representation of semantic knowledge in the human brain.
Nat Rev Neurosci. 2007 Dec;8(12):976-87.
Mr M, a patient with semantic dementia--a neurodegenerative disease that is characterized by the gradual deterioration of semantic memory--was being driven through the countryside to visit a friend and was able to remind his wife where to turn along the not-recently-travelled route. Then, pointing at the sheep in the field, he asked her "What are those things?" Prior to the onset of symptoms in his late 40s, this man had normal semantic memory. What has gone wrong in his brain to produce this dramatic and selective erosion of conceptual knowledge? [Abstract]

Lamb TD, Collin SP, Pugh EN
Evolution of the vertebrate eye: opsins, photoreceptors, retina and eye cup.
Nat Rev Neurosci. 2007 Dec;8(12):960-76.
Charles Darwin appreciated the conceptual difficulty in accepting that an organ as wonderful as the vertebrate eye could have evolved through natural selection. He reasoned that if appropriate gradations could be found that were useful to the animal and were inherited, then the apparent difficulty would be overcome. Here, we review a wide range of findings that capture glimpses of the gradations that appear to have occurred during eye evolution, and provide a scenario for the unseen steps that have led to the emergence of the vertebrate eye. [Abstract]

Schmucker D
Molecular diversity of Dscam: recognition of molecular identity in neuronal wiring.
Nat Rev Neurosci. 2007 Dec;8(12):915-20.
Our understanding of how the enormously complex task of interconnecting millions of nerve cells is accomplished remains rudimentary. What molecular mechanisms control its exquisite specificity? Can we pinpoint single molecular interactions that might help to explain some of the specificity requirements that underlie neuronal wiring? A series of recent studies on the molecular diversity of the Drosophila melanogaster cell-surface receptor Down syndrome cell-adhesion molecule (Dscam) provide one exceptional example of a novel mechanistic model of neuronal-wiring specificity, progressing from structural studies of single protein-protein interactions to biochemical analysis in vitro and to an understanding of complex neuronal differentiation at the single-cell or tissue levels. [Abstract]

Tzingounis AV, Wadiche JI
Glutamate transporters: confining runaway excitation by shaping synaptic transmission.
Nat Rev Neurosci. 2007 Dec;8(12):935-47.
Traditionally, glutamate transporters have been viewed as membrane proteins that harness the electrochemical gradient to slowly transport glutamate from the extracellular space into glial cells. However, recent studies have shown that glutamate transporters on glial and neuronal membranes also rapidly bind released glutamate to shape synaptic transmission. In this Review, we summarize the properties of glutamate transporters that influence synaptic transmission and are subject to regulation and plasticity. We highlight how the diversity of glutamate-transporter function relates to transporter location, density and affinity. [Abstract]

Martin S, Wilkinson KA, Nishimune A, Henley JM
Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction.
Nat Rev Neurosci. 2007 Dec;8(12):948-59.
Post-translational protein modifications are integral components of signalling cascades that enable cells to efficiently, rapidly and reversibly respond to extracellular stimuli. These modifications have crucial roles in the CNS, where the communication between neurons is particularly complex. SUMOylation is a post-translational modification in which a member of the small ubiquitin-like modifier (SUMO) family of proteins is conjugated to lysine residues in target proteins. It is well established that SUMOylation controls many aspects of nuclear function, but it is now clear that it is also a key determinant in many extranuclear neuronal processes, and it has also been implicated in a wide range of neuropathological conditions. [Abstract]

Gamper N, Shapiro MS
Regulation of ion transport proteins by membrane phosphoinositides.
Nat Rev Neurosci. 2007 Dec;8(12):921-34.
Over the past decade, there has been an explosion in the number of membrane transport proteins that have been shown to be sensitive to the abundance of phosphoinositides in the plasma membrane. These proteins include voltage-gated potassium and calcium channels, ion channels that mediate sensory and nociceptive responses, epithelial transport proteins and ionic exchangers. Each of the regulatory lipids is also under multifaceted regulatory control. Phosphoinositide modulation of membrane proteins in neurons often has a dramatic effect on neuronal excitability and synaptic transmitter release. The repertoire of lipid signalling mechanisms that regulate membrane proteins is intriguingly complex and provides a rich array of topics for neuroscience research. [Abstract]

Rost�ne W, Kitabgi P, Parsadaniantz SM
Chemokines: a new class of neuromodulator?
Nat Rev Neurosci. 2007 Nov;8(11):895-903.
Chemokines are not only found in the immune system or expressed in inflammatory conditions: they are constitutively present in the brain in both glial cells and neurons. Recently, the possibility has been raised that they might act as neurotransmitters or neuromodulators. Although the evidence is incomplete, emerging data show that chemokines have several of the characteristics that define neurotransmitters. Moreover, their physiological actions resemble those of neuromodulators in the sense that chemokines usually have few effects by themselves in basal conditions, but modify the induced release of neurotransmitters or neuropeptides. These findings, together with the pharmacological development of agonists and antagonists that are selective for chemokine receptors and can cross the blood-brain barrier, open a new era of research in neuroscience. [Abstract]

Squire LR, Wixted JT, Clark RE
Recognition memory and the medial temporal lobe: a new perspective.
Nat Rev Neurosci. 2007 Nov;8(11):872-83.
Recognition memory is widely viewed as consisting of two components, recollection and familiarity, which have been proposed to be dependent on the hippocampus and the adjacent perirhinal cortex, respectively. Here, we propose an alternative perspective: we suggest that the methods traditionally used to separate recollection from familiarity instead separate strong memories from weak memories. A review of work with humans, monkeys and rodents finds evidence for familiarity signals (as well as recollection signals) in the hippocampus and recollection signals (as well as familiarity signals) in the perirhinal cortex. We also indicate ways in which the functions of the medial temporal lobe structures are different, and suggest that these structures work together in a cooperative and complementary way. [Abstract]

Guthrie S
Patterning and axon guidance of cranial motor neurons.
Nat Rev Neurosci. 2007 Nov;8(11):859-71.
The cranial motor nerves control muscles involved in eye, head and neck movements, feeding, speech and facial expression. The generic and specific properties of cranial motor neurons depend on a matrix of rostrocaudal and dorsoventral patterning information. Repertoires of transcription factors, including Hox genes, confer generic and specific properties on motor neurons, and endow subpopulations at various axial levels with the ability to navigate to their targets. Cranial motor axon projections are guided by diffusible cues and aided by guideposts, such as nerve exit points, glial cells and muscle primordia. The recent identification of genes that are mutated in human cranial dysinnervation disorders is now shedding light on the functional consequences of perturbations of cranial motor neuron development. [Abstract]

Kauer JA, Malenka RC
Synaptic plasticity and addiction.
Nat Rev Neurosci. 2007 Nov;8(11):844-58.
Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems. [Abstract]

Wilkinson LS, Davies W, Isles AR
Genomic imprinting effects on brain development and function.
Nat Rev Neurosci. 2007 Nov;8(11):832-43.
In a small fraction of mammalian genes--at present estimated at less than 1% of the total--one of the two alleles that is inherited by the offspring is partially or completely switched off. The decision as to which one is silenced depends on which allele was inherited from the mother and which from the father. These idiosyncratic loci are known as imprinted genes, and their existence is an evolutionary enigma, as they effectively nullify the advantages of diploidy. Although they are small in number, these genes have important effects on physiology and behaviour, and many are expressed in the brain. There is increasing evidence that imprinted genes influence brain function and behaviour by affecting neurodevelopmental processes. [Abstract]

Murray RM, Morrison PD, Henquet C, Di Forti M
Cannabis, the mind and society: the hash realities.
Nat Rev Neurosci. 2007 Nov;8(11):885-95.
Cannabis has been known for at least 4,000 years to have profound effects on the mind--effects that have provoked dramatically divergent attitudes towards it. Some societies have regarded cannabis as a sacred boon for mankind that offers respite from the tribulations of everyday life, whereas others have demonized it as inevitably leading to 'reefer madness'. The debate between the protagonists and prohibitionists has recently been re-ignited, but unfortunately this debate continues mainly in ignorance of our new understanding of the effects of cannabis on the brain and of studies that have quantified the extent of the risks of long-term use. [Abstract]

Li Q, Lee JA, Black DL
Neuronal regulation of alternative pre-mRNA splicing.
Nat Rev Neurosci. 2007 Nov;8(11):819-31.
Alternative pre-mRNA splicing has an important role in the control of neuronal gene expression. Many neuronal proteins are structurally diversified through the differential inclusion and exclusion of sequences in the final spliced mRNA. Here, we discuss common mechanisms of splicing regulation and provide examples of how alternative splicing has important roles in neuronal development and mature neuron function. Finally, we describe regulatory proteins that control the splicing of some neuronally expressed transcripts. [Abstract]

Lipton SA
Pathologically activated therapeutics for neuroprotection.
Nat Rev Neurosci. 2007 Oct;8(10):803-8.
Many drugs that have been developed to treat neurodegenerative diseases fail to gain approval for clinical use because they are not well tolerated in humans. In this article, I describe a series of strategies for the development of neuroprotective therapeutics that are both effective and well tolerated. These strategies are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit. This approach has already met with success, and has led to the development of the potentially neuroprotective drug memantine, an N-methyl-D-aspartate (NMDA)-type and glutamate receptor antagonist. [Abstract]

Herzog ED
Neurons and networks in daily rhythms.
Nat Rev Neurosci. 2007 Oct;8(10):790-802.
Biological pacemakers dictate our daily schedules in physiology and behaviour. The molecules, cells and networks that underlie these circadian rhythms can now be monitored using long-term cellular imaging and electrophysiological tools, and initial studies have already suggested a theme--circadian clocks may be crucial for widespread changes in brain activity and plasticity. These daily changes can modify the amount or activity of available genes, transcripts, proteins, ions and other biologically active molecules, ultimately determining cellular properties such as excitability and connectivity. Recently discovered circadian molecules and cells provide preliminary insights into a network that adapts to predictable daily and seasonal changes while remaining robust in the face of other perturbations. [Abstract]

Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM
Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity.
Nat Rev Neurosci. 2007 Oct;8(10):766-75.
At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous molecule is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep-wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic. [Abstract]

Maden M
Retinoic acid in the development, regeneration and maintenance of the nervous system.
Nat Rev Neurosci. 2007 Oct;8(10):755-65.
Retinoic acid (RA) is involved in the induction of neural differentiation, motor axon outgrowth and neural patterning. Like other developmental molecules, RA continues to play a role after development has been completed. Elevated RA signalling in the adult triggers axon outgrowth and, consequently, nerve regeneration. RA is also involved in the maintenance of the differentiated state of adult neurons, and disruption of RA signalling in the adult leads to the degeneration of motor neurons (motor neuron disease), the development of Alzheimer's disease and, possibly, the development of Parkinson's disease. The data described here strongly suggest that RA could be used as a therapeutic molecule for the induction of axon regeneration and the treatment of neurodegeneration. [Abstract]

Piomelli D, Astarita G, Rapaka R
A neuroscientist's guide to lipidomics.
Nat Rev Neurosci. 2007 Oct;8(10):743-54.
Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses. [Abstract]

Bramham CR, Wells DG
Dendritic mRNA: transport, translation and function.
Nat Rev Neurosci. 2007 Oct;8(10):776-89.
Many cellular functions require the synthesis of a specific protein or functional cohort of proteins at a specific time and place in the cell. Local protein synthesis in neuronal dendrites is essential for understanding how neural activity patterns are transduced into persistent changes in synaptic connectivity during cortical development, memory storage and other long-term adaptive brain responses. Regional and temporal changes in protein levels are commonly coordinated by an asymmetric distribution of mRNAs. This Review attempts to integrate current knowledge of dendritic mRNA transport, storage and translation, placing particular emphasis on the coordination of regulation and function during activity-dependent synaptic plasticity in the adult mammalian brain. [Abstract]

Pridmore S
Therapeutic use of rTMS.
Nat Rev Neurosci. 2007 Sep 12; [Abstract]

Ridding MC, Rothwell JC
Therapeutic use of rTMS.
Nat Rev Neurosci. 2007 Sep 12; [Abstract]

Hyman SE
Can neuroscience be integrated into the DSM-V?
Nat Rev Neurosci. 2007 Sep;8(9):725-32.
To date, the diagnosis of mental disorders has been based on clinical observation, specifically: the identification of symptoms that tend to cluster together, the timing of the symptoms' appearance, and their tendency to resolve, recur or become chronic. The Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Disease, the manuals that specify these diagnoses and the criteria for making them, are currently undergoing revision. It is thus timely to ask whether neuroscience has progressed to the point that the next editions of these manuals can usefully incorporate information about brain structure and function. [Abstract]

Curtis MA, Faull RL, Eriksson PS
The effect of neurodegenerative diseases on the subventricular zone.
Nat Rev Neurosci. 2007 Sep;8(9):712-23.
During brain development, one of the most important structures is the subventricular zone (SVZ), from which most neurons are generated. In adulthood the SVZ maintains a pool of progenitor cells that continuously replace neurons in the olfactory bulb. Neurodegenerative diseases induce a substantial upregulation or downregulation of SVZ progenitor cell proliferation, depending on the type of disorder. Far from being a dormant layer, the SVZ responds to neurodegenerative disease in a way that makes it a potential target for therapeutic intervention. [Abstract]

Fox MD, Raichle ME
Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.
Nat Rev Neurosci. 2007 Sep;8(9):700-11.
The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease. [Abstract]

Kullmann DM, Lamsa KP
Long-term synaptic plasticity in hippocampal interneurons.
Nat Rev Neurosci. 2007 Sep;8(9):687-99.
Rapid memory formation relies, at least in part, on long-term potentiation (LTP) of excitatory synapses. Inhibitory interneurons of the hippocampus, which are essential for information processing, have recently been found to exhibit not one, but two forms of LTP. One form resembles LTP that occurs in pyramidal neurons, which depends on N-methyl-D-aspartate receptors and is triggered by coincident pre- and postsynaptic activity. The other depends on Ca2+ influx through glutamate receptors that preferentially open when the postsynaptic neuron is at rest. Here we review these contrasting forms of LTP and describe how they are mirrored by two forms of long-term depression. We further discuss how the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit. [Abstract]

Huang ZJ, Di Cristo G, Ango F
Development of GABA innervation in the cerebral and cerebellar cortices.
Nat Rev Neurosci. 2007 Sep;8(9):673-86.
In many areas of the vertebrate brain, such as the cerebral and cerebellar cortices, neural circuits rely on inhibition mediated by GABA (gamma-aminobutyric acid) to shape the spatiotemporal patterns of electrical signalling. The richness and subtlety of inhibition are achieved by diverse classes of interneurons that are endowed with distinct physiological properties. In addition, the axons of interneurons display highly characteristic and class-specific geometry and innervation patterns, and thereby distribute their output to discrete spatial domains, cell types and subcellular compartments in neural networks. The cellular and molecular mechanisms that specify and modify inhibitory innervation patterns are only just beginning to be understood. [Abstract]

Schacter DL, Addis DR, Buckner RL
Remembering the past to imagine the future: the prospective brain.
Nat Rev Neurosci. 2007 Sep;8(9):657-61.
A rapidly growing number of recent studies show that imagining the future depends on much of the same neural machinery that is needed for remembering the past. These findings have led to the concept of the prospective brain; an idea that a crucial function of the brain is to use stored information to imagine, simulate and predict possible future events. We suggest that processes such as memory can be productively re-conceptualized in light of this idea. [Abstract]

Ballatore C, Lee VM, Trojanowski JQ
Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.
Nat Rev Neurosci. 2007 Sep;8(9):663-72.
Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies. [Abstract]

Peelen MV, Downing PE
The neural basis of visual body perception.
Nat Rev Neurosci. 2007 Aug;8(8):636-48.
The human body, like the human face, is a rich source of socially relevant information about other individuals. Evidence from studies of both humans and non-human primates points to focal regions of the higher-level visual cortex that are specialized for the visual perception of the body. These body-selective regions, which can be dissociated from regions involved in face perception, have been implicated in the perception of the self and the 'body schema', the perception of others' emotions and the understanding of actions. [Abstract]

Recent Articles in Neuron

Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL
Disruption of large-scale brain systems in advanced aging.
Neuron. 2007 Dec 6;56(5):924-35.
Cognitive decline is commonly observed in advanced aging even in the absence of disease. Here we explore the possibility that normal aging is accompanied by disruptive alterations in the coordination of large-scale brain systems that support high-level cognition. In 93 adults aged 18 to 93, we demonstrate that aging is characterized by marked reductions in normally present functional correlations within two higher-order brain systems. Anterior to posterior components within the default network were most severely disrupted with age. Furthermore, correlation reductions were severe in older adults free from Alzheimer's disease (AD) pathology as determined by amyloid imaging, suggesting that functional disruptions were not the result of AD. Instead, reduced correlations were associated with disruptions in white matter integrity and poor cognitive performance across a range of domains. These results suggest that cognitive decline in normal aging arises from functional disruption in the coordination of large-scale brain systems that support cognition. [Abstract]

Ferezou I, Haiss F, Gentet LJ, Aronoff R, Weber B, Petersen CC
Spatiotemporal dynamics of cortical sensorimotor integration in behaving mice.
Neuron. 2007 Dec 6;56(5):907-23.
Tactile information is actively acquired and processed in the brain through concerted interactions between movement and sensation. Somatosensory input is often the result of self-generated movement during the active touch of objects, and conversely, sensory information is used to refine motor control. There must therefore be important interactions between sensory and motor pathways, which we chose to investigate in the mouse whisker sensorimotor system. Voltage-sensitive dye was applied to the neocortex of mice to directly image the membrane potential dynamics of sensorimotor cortex with subcolumnar spatial resolution and millisecond temporal precision. Single brief whisker deflections evoked highly distributed depolarizing cortical sensory responses, which began in the primary somatosensory barrel cortex and subsequently excited the whisker motor cortex. The spread of sensory information to motor cortex was dynamically regulated by behavior and correlated with the generation of sensory-evoked whisker movement. Sensory processing in motor cortex may therefore contribute significantly to active tactile sensory perception. [Abstract]

Milenkovic N, Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C, Lewin GR, Garratt AN
Nociceptive Tuning by Stem Cell Factor/c-Kit Signaling.
Neuron. 2007 Dec 6;56(5):893-906.
The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold and reduction in spiking rate of heat-sensitive nociceptors. Acute activation of c-Kit by its ligand, SCF, resulted in a reduced thermal threshold and potentiation of heat-activated currents in isolated small-diameter neurons and thermal hyperalgesia in mice. SCF-induced thermal hyperalgesia required the TRP family cation channel TRPV1. Lack of c-Kit signaling during development resulted in hypersensitivity of discrete mechanoreceptive neuronal subtypes. Thus, c-Kit can now be grouped with a small family of receptor tyrosine kinases, including c-Ret and TrkA, that control the transduction properties of sensory neurons. [Abstract]

Delaney AJ, Crane JW, Sah P
Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism.
Neuron. 2007 Dec 6;56(5):880-92.
The lateral division of the central amygdala (CeAL) is the target of ascending fibers from the pain-responsive and stress-responsive nuclei in the brainstem. We show that single fiber inputs from the nociceptive pontine parabrachial nucleus onto CeAL neurons form suprathreshold glutamatergic synapses with multiple release sites. Noradrenaline, acting at presynaptic alpha2 receptors, potently inhibits this synapse. This inhibition results from a decrease in the number of active release sites with no change in release probability. Introduction of a presynaptic scavenger of Gbetagamma subunits blocked the effects of noradrenaline, and botulinum toxin A reduced its effects, showing a direct action of betagamma subunits on the release machinery. These data illustrate a mechanism of presynaptic modulation where the output of a large multiple-release-site synapse is potently regulated by endogenously released noradrenaline and suggests that the CeA may be a target for the central nociceptive actions of noradrenaline. [Abstract]

Dudman JT, Tsay D, Siegelbaum SA
A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity.
Neuron. 2007 Dec 6;56(5):866-79.
Synaptic potentials originating at distal dendritic locations are severely attenuated when they reach the soma and, thus, are poor at driving somatic spikes. Nonetheless, distal inputs convey essential information, suggesting that such inputs may be important for compartmentalized dendritic signaling. Here we report a new plasticity rule in which stimulation of distal perforant path inputs to hippocampal CA1 pyramidal neurons induces long-term potentiation at the CA1 proximal Schaffer collateral synapses when the two inputs are paired at a precise interval. This subthreshold form of heterosynaptic plasticity occurs in the absence of somatic spiking but requires activation of both NMDA receptors and IP(3) receptor-dependent release of Ca(2+) from internal stores. Our results suggest that direct sensory information arriving at distal CA1 synapses through the perforant path provide compartmentalized, instructive signals that assess the saliency of mnemonic information propagated through the hippocampal circuit to proximal synapses. [Abstract]

Wu Y, Wang W, D�ez-Sampedro A, Richerson GB
Nonvesicular Inhibitory Neurotransmission via Reversal of the GABA Transporter GAT-1.
Neuron. 2007 Dec 6;56(5):851-65.
GABA transporters play an important but poorly understood role in neuronal inhibition. They can reverse, but this is widely thought to occur only under pathological conditions. Here we use a heterologous expression system to show that the reversal potential of GAT-1 under physiologically relevant conditions is near the normal resting potential of neurons and that reversal can occur rapidly enough to release GABA during simulated action potentials. We then use paired recordings from cultured hippocampal neurons and show that GABAergic transmission is not prevented by four methods widely used to block vesicular release. This nonvesicular neurotransmission was potently blocked by GAT-1 antagonists and was enhanced by agents that increase cytosolic [GABA] or [Na(+)] (which would increase GAT-1 reversal). We conclude that GAT-1 regulates tonic inhibition by clamping ambient [GABA] at a level high enough to activate high-affinity GABA(A) receptors and that transporter-mediated GABA release can contribute to phasic inhibition. [Abstract]

Sachse S, Rueckert E, Keller A, Okada R, Tanaka NK, Ito K, Vosshall LB
Activity-dependent plasticity in an olfactory circuit.
Neuron. 2007 Dec 6;56(5):838-50.
Olfactory sensory neurons (OSNs) form synapses with local interneurons and second-order projection neurons to form stereotyped olfactory glomeruli. This primary olfactory circuit is hard-wired through the action of genetic cues. We asked whether individual glomeruli have the capacity for stimulus-evoked plasticity by focusing on the carbon dioxide (CO(2)) circuit in Drosophila. Specialized OSNs detect this gas and relay the information to a dedicated circuit in the brain. Prolonged exposure to CO(2) induced a reversible volume increase in the CO(2)-specific glomerulus. OSNs showed neither altered morphology nor function after chronic exposure, but one class of inhibitory local interneurons showed significantly increased responses to CO(2). Two-photon imaging of the axon terminals of a single PN innervating the CO(2) glomerulus showed significantly decreased functional output following CO(2) exposure. Behavioral responses to CO(2) were also reduced after such exposure. We suggest that activity-dependent functional plasticity may be a general feature of the Drosophila olfactory system. [Abstract]

Samuels BA, Hsueh YP, Shu T, Liang H, Tseng HC, Hong CJ, Su SC, Volker J, Neve RL, Yue DT, Tsai LH
Cdk5 Promotes Synaptogenesis by Regulating the Subcellular Distribution of the MAGUK Family Member CASK.
Neuron. 2007 Dec 6;56(5):823-837.
Synaptogenesis is a highly regulated process that underlies formation of neural circuitry. Considerable work has demonstrated the capability of some adhesion molecules, such as SynCAM and Neurexins/Neuroligins, to induce synapse formation in vitro. Furthermore, Cdk5 gain of function results in an increased number of synapses in vivo. To gain a better understanding of how Cdk5 might promote synaptogenesis, we investigated potential crosstalk between Cdk5 and the cascade of events mediated by synapse-inducing proteins. One protein recruited to developing terminals by SynCAM and Neurexins/Neuroligins is the MAGUK family member CASK. We found that Cdk5 phosphorylates and regulates CASK distribution to membranes. In the absence of Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and thus fails to interact with essential presynaptic components. Functional consequences include alterations in calcium influx. Mechanistically, Cdk5 regulates the interaction between CASK and liprin-alpha. These results provide a molecular explanation of how Cdk5 can promote synaptogenesis. [Abstract]

Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F
Gating of Sema3E/PlexinD1 Signaling by Neuropilin-1 Switches Axonal Repulsion to Attraction during Brain Development.
Neuron. 2007 Dec 6;56(5):807-22.
The establishment of functional neural circuits requires the guidance of axons in response to the actions of secreted and cell-surface molecules such as the semaphorins. Semaphorin 3E and its receptor PlexinD1 are expressed in the brain, but their functions are unknown. Here, we show that Sema3E/PlexinD1 signaling plays an important role in initial development of descending axon tracts in the forebrain. Early errors in axonal projections are reflected in behavioral deficits in Sema3E null mutant mice. Two distinct signaling mechanisms can be distinguished downstream of Sema3E. On corticofugal and striatonigral neurons expressing PlexinD1 but not Neuropilin-1, Sema3E acts as a repellent. In contrast, on subiculo-mammillary neurons coexpressing PlexinD1 and Neuropilin-1, Sema3E acts as an attractant. The extracellular domain of Neuropilin-1 is sufficient to convert repulsive signaling by PlexinD1 to attraction. Our data therefore reveal a "gating" function of neuropilins in semaphorin-plexin signaling during the assembly of forebrain neuronal circuits. [Abstract]

Ting CY, Herman T, Yonekura S, Gao S, Wang J, Serpe M, O'Connor MB, Zipursky SL, Lee CH
Tiling of r7 axons in the Drosophila visual system is mediated both by transduction of an activin signal to the nucleus and by mutual repulsion.
Neuron. 2007 Dec 6;56(5):793-806.
The organization of neuronal wiring into layers and columns is a common feature of both vertebrate and invertebrate brains. In the Drosophila visual system, each R7 photoreceptor axon projects within a single column to a specific layer of the optic lobe. We refer to the restriction of terminals to single columns as tiling. In a genetic screen based on an R7-dependent behavior, we identified the Activin receptor Baboon and the nuclear import adaptor Importin-alpha3 as being required to prevent R7 axon terminals from overlapping with the terminals of R7s in neighboring columns. This tiling function requires the Baboon ligand, dActivin, the transcription factor, dSmad2, and retrograde transport from the growth cone to the R7 nucleus. We propose that dActivin is an autocrine signal that restricts R7 growth cone motility, and we demonstrate that it acts in parallel with a paracrine signal that mediates repulsion between R7 terminals. [Abstract]

Roelfsema PR, Tolboom M, Khayat PS
Different Processing Phases for Features, Figures, and Selective Attention in the Primary Visual Cortex.
Neuron. 2007 Dec 6;56(5):785-792.
Our visual system imposes structure onto images that usually contain a diversity of surfaces, contours, and colors. Psychological theories propose that there are multiple steps in this process that occur in hierarchically organized regions of the cortex: early visual areas register basic features, higher areas bind them into objects, and yet higher areas select the objects that are relevant for behavior. Here we test these theories by recording from the primary visual cortex (area V1) of monkeys. We demonstrate that the V1 neurons first register the features (at a latency of 48 ms), then segregate figures from the background (after 57 ms), and finally select relevant figures over irrelevant ones (after 137 ms). We conclude that the psychological processing stages map onto distinct time episodes that unfold in the visual cortex after the presentation of a new stimulus, so that area V1 may contribute to all these processing steps. [Abstract]

Buzs�ki G, Kaila K, Raichle M
Inhibition and brain work.
Neuron. 2007 Dec 6;56(5):771-83.
The major part of the brain's energy budget ( approximately 60%-80%) is devoted to its communication activities. While inhibition is critical to brain function, relatively little attention has been paid to its metabolic costs. Understanding how inhibitory interneurons contribute to brain energy consumption (brain work) is not only of interest in understanding a fundamental aspect of brain function but also in understanding functional brain imaging techniques which rely on measurements related to blood flow and metabolism. Herein we examine issues relevant to an assessment of the work performed by inhibitory interneurons in the service of brain function. [Abstract]

Glykys J, Mody I
Activation of GABA(A) Receptors: Views from Outside the Synaptic Cleft.
Neuron. 2007 Dec 6;56(5):763-70.
Some GABA(A) receptors (GABA(A)Rs) are activated by low transmitter levels present in the extracellular space and generate an uninterrupted conductance referred to as "tonic." This tonic conductance is highly sensitive to all factors regulating the amount of GABA surrounding the neurons. Only a few GABA(A)Rs with particular subunit combinations are well suited to mediate the tonic conductance. These same receptors constitute important and specific targets for various endogenous and exogenous neuroactive compounds and possible therapeutic targets. [Abstract]

Kleinfeld D, Waters J
Wilder Penfield in the Age of YouTube: Visualizing the Sequential Activation of Sensorimotor Areas across Neocortex.
Neuron. 2007 Dec 6;56(5):760-2.
Flow of electrical activity across neocortex is essential for many sensorimotor tasks. Whether this flow is localized or spreads widely is unknown. Ferezou et al., imaging activity across the cortical mantle in awake mice, show in this issue of Neuron that touch by a single vibrissa leads to a rapid depolarization of primary sensory and motor areas that subsequently spreads across most of cortex. [Abstract]

Tully K, Li Y, Bolshakov VY
Keeping in check painful synapses in central amygdala.
Neuron. 2007 Dec 6;56(5):757-9.
Glutamatergic projections from the parabrachial nucleus to the central amygdala are implicated in pain transmission. In this issue of Neuron, Delaney et al. identify a new form of adrenergic modulation at these synapses, demonstrating that noradrenaline-induced suppression of glutamate release is mediated by a decrease in the number of sites of synaptic transmission without changes in probability of release. [Abstract]

Shapley R
Early vision is early in time.
Neuron. 2007 Dec 6;56(5):755-6.
Roelfsema, Tolboom, and Khayat have found that neurons in primary visual cortex, V1, increase their spike firing rates to signal image segmentation and attention. V1 responses were in a temporal sequence: first to image motion, next to segmentation, last to attentional signals. The involvement of V1 with segmentation and attention suggests modifying the hierarchical view of visual perception. [Abstract]

Suzuki S, Grabowecky M
Long-term speeding in perceptual switches mediated by attention-dependent plasticity in cortical visual processing.
Neuron. 2007 Nov 22;56(4):741-53.
Binocular rivalry has been extensively studied to understand the mechanisms that control switches in visual awareness and much has been revealed about the contributions of stimulus and cognitive factors. Because visual processes are fundamentally adaptive, however, it is also important to understand how experience alters the dynamics of perceptual switches. When observers viewed binocular rivalry repeatedly over many days, the rate of perceptual switches increased as much as 3-fold. This long-term rivalry speeding exhibited a pattern of image-feature specificity that ruled out primary contributions from strategic and nonsensory factors and implicated neural plasticity occurring in both low- and high-level visual processes in the ventral stream. Furthermore, the speeding occurred only when the rivaling patterns were voluntarily attended, suggesting that the underlying neural plasticity selectively engages when stimuli are behaviorally relevant. Long-term rivalry speeding may thus reflect broader mechanisms that facilitate quick assessments of signals that contain multiple behaviorally relevant interpretations. [Abstract]

Raizada RD, Poldrack RA
Selective Amplification of Stimulus Differences during Categorical Processing of Speech.
Neuron. 2007 Nov 22;56(4):726-40.
The brain's perceptual stimuli are constantly changing: some of these changes are treated as invariances and are suppressed, whereas others are selectively amplified, giving emphasis to the distinctions that matter most. The starkest form of such amplification is categorical perception. In speech, for example, a continuum of phonetic stimuli gets carved into perceptually distinct categories. We used fMRI to measure the degree to which this process of selective amplification takes place. The most categorically processing area was the left supramarginal gyrus: stimuli from different phonetic categories, when presented together in a contrasting pair, were neurally amplified more than two-fold. Low-level auditory cortical areas, however, showed comparatively little amplification of changes that crossed category boundaries. Selective amplification serves to emphasize key stimulus differences, thereby shaping perceptual categories. The approach presented here provides a quantitative way to measure the degree to which such processing is taking place. [Abstract]

Urbain N, Desch�nes M
Motor cortex gates vibrissal responses in a thalamocortical projection pathway.
Neuron. 2007 Nov 22;56(4):714-25.
Higher-order thalamic nuclei receive input from both the cerebral cortex and prethalamic sensory pathways. However, at rest these nuclei appear silent due to inhibitory input from extrathalamic regions, and it has therefore remained unclear how sensory gating of these nuclei takes place. In the rodent, the ventral division of the zona incerta (ZIv) serves as a relay station within the paralemniscal thalamocortical projection pathway for whisker-driven motor activity. Most, perhaps all, ZIv neurons are GABAergic, and recent studies have shown that these cells participate in a feedforward inhibitory circuit that blocks sensory transmission in the thalamus. The present study provides evidence that the stimulation of the vibrissa motor cortex suppresses vibrissal responses in ZIv via an intra-incertal GABAergic circuit. These results provide support for the proposal that sensory transmission operates via a top-down disinhibitory mechanism that is contingent on motor activity. [Abstract]

Disney AA, Aoki C, Hawken MJ
Gain modulation by nicotine in macaque v1.
Neuron. 2007 Nov 22;56(4):701-13.
Acetylcholine is a ubiquitous cortical neuromodulator implicated in cognition. In order to understand the potential for acetylcholine to play a role in visual attention, we studied nicotinic acetylcholine receptor (nAChR) localization and function in area V1 of the macaque. We found nAChRs presynaptically at thalamic synapses onto excitatory, but not inhibitory, neurons in the primary thalamorecipient layer 4c. Furthermore, consistent with the release enhancement suggested by this localization, we discovered that nicotine increases responsiveness and lowers contrast threshold in layer 4c neurons. We also found that nAChRs are expressed by GABAergic interneurons in V1 but rarely by pyramidal neurons, and that nicotine suppresses visual responses outside layer 4c. All sensory systems incorporate gain control mechanisms, or processes which dynamically alter input/output relationships. We demonstrate that at the site of thalamic input to visual cortex, the effect of this nAChR-mediated gain is an enhancement of the detection of visual stimuli. [Abstract]

Olveczky BP, Baccus SA, Meister M
Retinal adaptation to object motion.
Neuron. 2007 Nov 22;56(4):689-700.
Due to fixational eye movements, the image on the retina is always in motion, even when one views a stationary scene. When an object moves within the scene, the corresponding patch of retina experiences a different motion trajectory than the surrounding region. Certain retinal ganglion cells respond selectively to this condition, when the motion in the cell's receptive field center is different from that in the surround. Here we show that this response is strongest at the very onset of differential motion, followed by gradual adaptation with a time course of several seconds. Different subregions of a ganglion cell's receptive field can adapt independently. The circuitry responsible for differential motion adaptation lies in the inner retina. Several candidate mechanisms were tested, and the adaptation most likely results from synaptic depression at the synapse from bipolar to ganglion cell. Similar circuit mechanisms may act more generally to emphasize novel features of a visual stimulus. [Abstract]

Serulle Y, Zhang S, Ninan I, Puzzo D, McCarthy M, Khatri L, Arancio O, Ziff EB
A GluR1-cGKII Interaction Regulates AMPA Receptor Trafficking.
Neuron. 2007 Nov 22;56(4):670-88.
Trafficking of AMPA receptors (AMPARs) is regulated by specific interactions of the subunit intracellular C-terminal domains (CTDs) with other proteins, but the mechanisms involved in this process are still unclear. We have found that the GluR1 CTD binds to cGMP-dependent protein kinase II (cGKII) adjacent to the kinase catalytic site. Binding of GluR1 is increased when cGKII is activated by cGMP. cGKII and GluR1 form a complex in the brain, and cGKII in this complex phosphorylates GluR1 at S845, a site also phosphorylated by PKA. Activation of cGKII by cGMP increases the surface expression of AMPARs at extrasynaptic sites. Inhibition of cGKII activity blocks the surface increase of GluR1 during chemLTP and reduces LTP in the hippocampal slice. This work identifies a pathway, downstream from the NMDA receptor (NMDAR) and nitric oxide (NO), which stimulates GluR1 accumulation in the plasma membrane and plays an important role in synaptic plasticity. [Abstract]

Zhou KM, Dong YM, Ge Q, Zhu D, Zhou W, Lin XG, Liang T, Wu ZX, Xu T
PKA Activation Bypasses the Requirement for UNC-31 in the Docking of Dense Core Vesicles from C. elegans Neurons.
Neuron. 2007 Nov 22;56(4):657-69.
The nematode C. elegans provides a powerful model system for exploring the molecular basis of synaptogenesis and neurotransmission. However, the lack of direct functional assays of release processes has largely prevented an in depth understanding of the mechanism of vesicular exocytosis and endocytosis in C. elegans. We address this technical limitation by developing direct electrophysiological assays, including membrane capacitance and amperometry measurements, in primary cultured C. elegans neurons. In addition, we have succeeded in monitoring the docking and fusion of single dense core vesicles (DCVs) employing total internal reflection fluorescence microscopy. With these approaches and mutant perturbation analysis, we provide direct evidence that UNC-31 is required for the docking of DCVs at the plasma membrane. Interestingly, the defect in DCV docking caused by UNC-31 mutation can be fully rescued by PKA activation. We also demonstrate that UNC-31 is required for UNC-13-mediated augmentation of DCV exocytosis. [Abstract]

Xie Z, Srivastava DP, Photowala H, Kai L, Cahill ME, Woolfrey KM, Shum CY, Surmeier DJ, Penzes P
Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines.
Neuron. 2007 Nov 22;56(4):640-56.
Activity-dependent rapid structural and functional modifications of central excitatory synapses contribute to synapse maturation, experience-dependent plasticity, and learning and memory and are associated with neurodevelopmental and psychiatric disorders. However, the signal transduction mechanisms that link glutamate receptor activation to intracellular effectors that accomplish structural and functional plasticity are not well understood. Here we report that NMDA receptor activation in pyramidal neurons causes CaMKII-dependent phosphorylation of the guanine-nucleotide exchange factor (GEF) kalirin-7 at residue threonine 95, regulating its GEF activity, leading to activation of small GTPase Rac1 and rapid enlargement of existing spines. Kalirin-7 also interacts with AMPA receptors and controls their synaptic expression. By demonstrating that kalirin expression and spine localization are required for activity-dependent spine enlargement and enhancement of AMPAR-mediated synaptic transmission, our study identifies a signaling pathway that controls structural and functional spine plasticity. [Abstract]

Gunnersen JM, Kim MH, Fuller SJ, De Silva M, Britto JM, Hammond VE, Davies PJ, Petrou S, Faber ES, Sah P, Tan SS
Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons.
Neuron. 2007 Nov 22;56(4):621-39.
Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity. [Abstract]

Lewcock JW, Genoud N, Lettieri K, Pfaff SL
The Ubiquitin Ligase Phr1 Regulates Axon Outgrowth through Modulation of Microtubule Dynamics.
Neuron. 2007 Nov 22;56(4):604-20.
To discover new genes involved in axon navigation, we conducted a forward genetic screen for recessive alleles affecting motor neuron pathfinding in GFP reporter mice mutagenized with ENU. In Magellan mutant embryos, motor axons were error prone and wandered inefficiently at choice points within embryos, but paradoxically responded to guidance cues with normal sensitivity in vitro. We mapped the Magellan mutation to the Phr1 gene encoding a large multidomain E3 ubiquitin ligase. Phr1 is associated with the microtubule cytoskeleton within neurons and selectively localizes to axons but is excluded from growth cones. Motor and sensory neurons from Magellan mutants display abnormal morphologies due to a breakdown in the polarized distribution of components that segregate between axons and growth cones. The Magellan phenotype can be reversed by stabilizing microtubules with taxol or inhibiting p38MAPK activity. Thus, efficacious pathfinding requires Phr1 activity for coordinating the cytoskeletal organization that distinguishes axons from growth cones. [Abstract]

Godinho L, Williams PR, Claassen Y, Provost E, Leach SD, Kamermans M, Wong RO
Nonapical symmetric divisions underlie horizontal cell layer formation in the developing retina in vivo.
Neuron. 2007 Nov 22;56(4):597-603.
Symmetric cell divisions have been proposed to rapidly increase neuronal number late in neurogenesis, but how critical this mode of division is to establishing a specific neuronal layer is unknown. Using in vivo time-lapse imaging methods, we discovered that in the laminated zebrafish retina, the horizontal cell (HC) layer forms quickly during embryonic development upon division of a precursor cell population. The precursor cells morphologically resemble immature, postmitotic HCs and express HC markers such as ptf1a and Prox1 prior to division. These precursors undergo nonapical symmetric division at the laminar location where mature HCs contact photoreceptors. Strikingly, the precursor cell type we observed generates exclusively HCs. We have thus identified a dedicated HC precursor, and our findings suggest a mechanism of neuronal layer formation whereby the location of mitosis could facilitate rapid contact between synaptic partners. [Abstract]

Kim SJ, Linden DJ
Ubiquitous plasticity and memory storage.
Neuron. 2007 Nov 22;56(4):582-92.
To date, most hypotheses of memory storage in the mammalian brain have focused upon long-term synaptic potentiation and depression (LTP and LTD) of fast glutamatergic excitatory postsynaptic currents (EPSCs). In recent years, it has become clear that many additional electrophysiological components of neurons, from electrical synapses to glutamate transporters to voltage-sensitive ion channels, can also undergo use-dependent long-term plasticity. Models of memory storage that incorporate this full range of demonstrated electrophysiological plasticity are better able to account for both the storage of memory in neuronal networks and the complexities of memory storage, indexing, and recall as measured behaviorally. [Abstract]

Griffiths TD
Sorting out sound.
Neuron. 2007 Nov 22;56(4):580-1.
Speech analysis is a prototypical categorical mechanism that has been examined behaviorally in work going back to Haskins Laboratory studies in the 1950s: such work examined the perception of continua between phonemes and demonstrated sharp discontinuities consistent with categorical perception. In this issue of Neuron, Raizada and Poldrack examine analysis mechanisms for such processing by measurement of the fMRI BOLD response in the boundary region between different phonemes and argue for a specific amplification mechanism for this type of categorical perception. [Abstract]

Diamond ME, Ahissar E
When outgoing and incoming signals meet: new insights from the zona incerta.
Neuron. 2007 Nov 22;56(4):578-9.
In the sense of touch, it is the motion of the sensory receptors themselves that leads to an afferent signal-whether these receptors are in our fingertips sliding along a surface or a rat's whiskers palpating an object. Afferent signals can be correctly interpreted only if the sensory system receives information about the brain's own motor output. In this issue of Neuron, Urbain and Desch�nes provide new insights into the physiological and anatomical interplay between tactile and motor signals in rats. [Abstract]

Recent Articles in Trends in Neurosciences

Jo�ls M, Karst H, Derijk R, de Kloet ER
The coming out of the brain mineralocorticoid receptor.
Trends Neurosci. 2007 Nov 30;
Corticosteroids - secreted after stress - have profound effects on brain and behavior. These effects are mediated by mineralocorticoid and glucocorticoid receptors, which are abundantly expressed in limbic neurons. The role of mineralocorticoid receptors in higher brain functions has never been well understood. Here we argue that the recently discovered low-affinity membrane version of the mineralocorticoid receptor contributes to the initial phase of the stress reaction; this is complemented by the glucocorticoid receptor which terminates the stress response. This concept may explain why human carriers of a mineralocorticoid receptor gene variant display enhanced neuroendocrine and autonomic responsiveness to a psychological stressor. [Abstract]

Sherman LS, Back SA
A 'GAG' reflex prevents repair of the damaged CNS.
Trends Neurosci. 2007 Nov 30;
The extracellular matrix of the central nervous system (CNS) serves as both a supporting structure for cells and a rich source of signaling molecules that can influence cell proliferation, survival, migration and differentiation. A large proportion of this matrix is composed of proteoglycans-proteins with long chains of polysaccharides, called glycosaminoglycans (GAGs), covalently attached. Although many of the activities of proteoglycans depend on their core proteins, GAGs themselves can influence cell signaling. Here we review accumulating evidence that two GAGs, chondroitin sulfate and hyaluronan, play essential roles during nervous system development but also accumulate in chronic CNS lesions and inhibit axonal regeneration and remyelination, making them significant hindrances to CNS repair. We propose that the balance between the synthesis and degradation of these molecules dictates, in part, how regeneration and recovery from CNS damage occurs. [Abstract]

Hankins MW, Peirson SN, Foster RG
Melanopsin: an exciting photopigment.
Trends Neurosci. 2007 Dec 2;
The discovery that mice lacking rods and cones are capable of regulating their circadian rhythms by light provided the conceptual framework for the discovery of an entirely new photoreceptor system within the mammalian eye. We now know that a small subset of retinal ganglion cells are directly photosensitive and utilize an opsin/vitamin A-based photopigment called melanopsin maximally sensitive in the blue part of the spectrum. We also know that these photosensitive retinal ganglion cells mediate a broad range of physiological responses to light, ranging from the regulation of circadian rhythms to pupil constriction. Most recently, it has become clear that the melanopsins are only distantly related to visual pigments and in terms of their biochemistry share more in common with invertebrate photopigments. Here we outline the discovery of this remarkable new photoreceptor system, review the structure of melanopsin and conclude with a working model of melanopsin phototransduction. [Abstract]

Tait MJ, Saadoun S, Bell BA, Papadopoulos MC
Water movements in the brain: role of aquaporins.
Trends Neurosci. 2007 Dec 2;
About 80% of the brain is water. This review discusses the importance of the three brain water-channel proteins (AQP1, AQP4, AQP9) in brain physiology. AQP1 is expressed in the choroid plexus and participates in forming cerebrospinal fluid. AQP4, found in astrocyte foot processes, glia limitans and ependyma, facilitates water movement into and out of the brain, accelerates astrocyte migration and alters neuronal activity. Recently, AQP4 autoantibodies were discovered in patients with neuromyelitis optica, a demyelinating disease, and are now being used to diagnose this condition. AQP9 is present in some glia and neurons, but its function is unclear. Finally, we discuss how the discovery of AQP activators and inhibitors will be the next major step in this field. [Abstract]

Friel DD, Chiel HJ
Calcium dynamics: analyzing the Ca(2+) regulatory network in intact cells.
Trends Neurosci. 2007 Dec 2;
Calcium signaling is critical for all cells. As a free ion (Ca(2+)), calcium links many physiological stimuli to their intracellular effectors by interacting with binding proteins whose occupancy determines the cellular effect of stimulation. Because binding site occupancy depends on the history of Ca(2+) concentration ([Ca(2+)]), Ca(2+) dynamics are critical. Calcium dynamics depend on the functional interplay between Ca(2+) transport and buffering systems whose activities depend nonlinearly on [Ca(2+)]. Thus, understanding Ca(2+) dynamics requires detailed information about these Ca(2+) handling systems and their regulation in intact cells. However, effective methods for measuring and characterizing intracellular Ca(2+) handling have not been available until recently. Using concepts relating voltage-gated ion-channel activity to membrane potential dynamics, we developed such methods to analyze Ca(2+) fluxes in intact cells. Here we describe this approach and applications to understanding depolarization-induced Ca(2+) responses in sympathetic neurons. [Abstract]

Gao FB
Posttranscriptional control of neuronal development by microRNA networks.
Trends Neurosci. 2007 Dec 1;
The proper development of the nervous system requires precise spatial and temporal control of gene expression at both the transcriptional and translational levels. In different experimental model systems, microRNAs (miRNAs) - a class of small, endogenous, noncoding RNAs that control the translation and stability of many mRNAs - are emerging as important regulators of various aspects of neuronal development. Further dissection of the in vivo physiological functions of individual miRNAs promises to offer novel mechanistic insights into the gene regulatory networks that ensure the precise assembly of a functional nervous system. [Abstract]

St Laurent G, Wahlestedt C
Noncoding RNAs: couplers of analog and digital information in nervous system function?
Trends Neurosci. 2007 Dec;30(12):612-21.
The mammalian nervous system expresses numerous noncoding RNAs (ncRNAs). We propose that ncRNAs are capable of coupling the digital information universe of nucleic acids with the analog universe of cellular protein interactions. ncRNAs could contribute to the success of the organism's information processing in several ways. First, ncRNAs would allow for efficient coupling of energy with information, wherein less energy is required to represent and process more information, condensed in analog and digital form, into smaller spatial and temporal domains, ideal for the environments found in neural tissues. Second, ncRNAs would permit the rapid acquisition of information from the environment, along with the rapid flexible processing and elimination of that information when it is no longer necessary. Third, ncRNAs would facilitate accelerated evolution of an organism's information content and functional computational systems. This emerging panorama might open new dimensions of information processing in the nervous system. [Abstract]

Bentivoglio M, Kristensson K
Neural-immune interactions in disorders of sleep-wakefulness organization.
Trends Neurosci. 2007 Dec;30(12):645-52.
Novel findings on the effects of inflammatory molecules on neuronal circuits, and on molecular interactions between immunity and sleep, in health and disease, shed light on the pathogenesis of disorders of past (encephalitis lethargica) and present concern (human African trypanosomiasis and narcolepsy), which share alterations in sleep-wakefulness transitions. Although these three disorders differ in etiology, synaptic interactions with immune-response-derived molecules could play a pathogenetic role. Knowledge obtained on neural-immune interplay during senescence also has implications for age-related sleep dysregulation, which is common in the elderly population. Altogether, the data indicate that cell groups implicated in the regulation of sleep and wakefulness, circadian timing, and their interactions could be sensitive to synaptic effects of immune molecules. [Abstract]

Barbour B, Brunel N, Hakim V, Nadal JP
What can we learn from synaptic weight distributions?
Trends Neurosci. 2007 Dec;30(12):622-629.
Much research effort into synaptic plasticity has been motivated by the idea that modifications of synaptic weights (or strengths or efficacies) underlie learning and memory. Here, we examine the possibility of exploiting the statistics of experimentally measured synaptic weights to deduce information about the learning process. Analysing distributions of synaptic weights requires a theoretical framework to interpret the experimental measurements, but the results can be unexpectedly powerful, yielding strong constraints on possible learning theories as well as information that is difficult to obtain by other means, such as the information storage capacity of a cell. We review the available experimental and theoretical techniques as well as important open issues. [Abstract]

Rodr�guez-Moreno A, Sihra TS
Kainate receptors with a metabotropic modus operandi.
Trends Neurosci. 2007 Dec;30(12):630-7.
Kainate receptors (KARs), together with AMPA and NMDA, are typically described as ionotropic glutamate receptors. The functions of KARs have begun to be elucidated only in the last decade. Although some the actions of KARs are classically ionotropic, surprisingly others seem to involve the activation of second-messenger cascades and invoke metabotropic roles for this type of glutamate receptor. In this review, we describe these metabotropic actions of KARs in relation to the putative signalling cascades involved. Although it is still a mystery how KARs activate G proteins to stimulate second-messenger cascades, intriguingly, in very recent studies, specific subunits of KARs have been demonstrated to associate with G proteins. Altogether, the body of evidence supports the hypothesis that, together with the canonical ionotropic operation, KARs expedite long-lasting signalling by novel metabotropic modes of action. [Abstract]

J��skel�inen IP, Ahveninen J, Belliveau JW, Raij T, Sams M
Short-term plasticity in auditory cognition.
Trends Neurosci. 2007 Dec;30(12):653-61.
Converging lines of evidence suggest that auditory system short-term plasticity can enable several perceptual and cognitive functions that have been previously considered as relatively distinct phenomena. Here we review recent findings suggesting that auditory stimulation, auditory selective attention and cross-modal effects of visual stimulation each cause transient excitatory and (surround) inhibitory modulations in the auditory cortex. These modulations might adaptively tune hierarchically organized sound feature maps of the auditory cortex (e.g. tonotopy), thus filtering relevant sounds during rapidly changing environmental and task demands. This could support auditory sensory memory, pre-attentive detection of sound novelty, enhanced perception during selective attention, influence of visual processing on auditory perception and longer-term plastic changes associated with perceptual learning. [Abstract]

Cariboni A, Maggi R, Parnavelas JG
From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons.
Trends Neurosci. 2007 Dec;30(12):638-44.
Gonadotropin-releasing hormone (GnRH) neurons, a small number of cells dispersed in the hypothalamic region of the basal forebrain, play an important role in reproductive function. These neurons originate in the nasal placode and migrate, first in the nasal compartment, then through the cribriform plate and finally through the basal forebrain, before they attain their positions in the hypothalamus. Their movement through changing molecular environments suggests that numerous factors are involved in different phases of their migration. In humans, failure of GnRH neurons to migrate normally results in delayed or absent pubertal maturation and infertility. Advances in genetic and molecular biologic techniques in this decade have allowed us to gain insights into several molecules that affect the migration of GnRH neurons and, consequently, play a role in the establishment and maintenance of reproductive function. [Abstract]

Chang N, El-Hayek YH, Gomez E, Wan Q
Phosphatase PTEN in neuronal injury and brain disorders.
Trends Neurosci. 2007 Nov;30(11):581-586.
The phosphatase and tensin homologue PTEN was originally identified as a tumor suppressor. In the CNS, mutation or inactivation of PTEN is best known for playing a tumorigenic role in the molecular pathogenesis of glioblastoma. However, recent studies show that PTEN is associated with several brain diseases other than cancer, suggesting a broader role of PTEN in CNS pathophysiology. Here, we review the evidence for the crucial involvement of PTEN in neuronal injury as well as in neurological and psychiatric disorders, and discuss the potential of PTEN as a molecular target for the development of a novel CNS therapeutic strategy. [Abstract]

Toonen RF, Verhage M
Munc18-1 in secretion: lonely Munc joins SNARE team and takes control.
Trends Neurosci. 2007 Nov;30(11):564-72.
SNARE proteins and the Sec1/Munc18 (SM) protein, Munc18-1, are essential components of the mammalian secretion machinery. Until recently, quite divergent working models existed for the central but rather isolated role of Munc18-1 in secretion and its relation to the SNAREs. New studies now solve old discrepancies, bring consensus among SM-SNARE interactions and emphasize how closely these proteins work together. Together, SM and SNARE proteins control each step in the exocytotic pathway as a team. Munc18-1 operates as the chief commander of the exocytotic SNARE team, making teamwork more efficient, working with specific team members on specific jobs, reducing promiscuity with members of noncognate teams, and adjusting team efforts as a function of recent history and environmental cues (presynaptic receptor activation). [Abstract]

Hegde AN, Upadhya SC
The ubiquitin-proteasome pathway in health and disease of the nervous system.
Trends Neurosci. 2007 Nov;30(11):587-95.
In recent years, proteolysis by the ubiquitin-proteasome pathway has attained prominence as a new molecular mechanism that regulates many vital functions of the nervous system, including development of synaptic connections and synaptic plasticity. Here, we review the latest findings on the role of proteolysis in sculpting the nervous system through control of axonal growth, axonal and dendritic pruning, and regulation of synaptic size and number. We also discuss how protein degradation functions in synaptic plasticity and the roles of local proteolysis in neuronal compartments. In addition, we describe how proteolysis is associated with Alzheimer's disease and ataxia. Furthermore, we highlight the recent approaches that exploit components of the ubiquitin-proteasome pathway for amelioration of these diseases in animal models. [Abstract]

Biber K, Neumann H, Inoue K, Boddeke HW
Neuronal 'On' and 'Off' signals control microglia.
Trends Neurosci. 2007 Nov;30(11):596-602.
Recent findings indicate that neurons are not merely passive targets of microglia but rather control microglial activity. The variety of different signals that neurons use to control microglia can be divided into two categories: 'Off' signals constitutively keep microglia in their resting state and antagonize proinflammatory activity. 'On' signals are inducible and include purines, chemokines, glutamate. They instruct microglia activation under pathological conditions towards a beneficial or detrimental phenotype. Various neuronal signaling molecules thus actively control microglia function, thereby contribute to the inflammatory milieu of the central nervous system. Thus, neurons should be envisaged as key immune modulators in the brain. [Abstract]

Dib-Hajj SD, Cummins TR, Black JA, Waxman SG
From genes to pain: Na(v)1.7 and human pain disorders.
Trends Neurosci. 2007 Nov;30(11):555-563.
Gain-of-function mutations or dysregulated expression of voltage-gated sodium channels can produce neuronal hyperexcitability, leading to acute or chronic pain. The sodium channel Na(v)1.7 is expressed preferentially in most slowly conducting nociceptive neurons and in sympathetic neurons. Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain. The contribution of Na(v)1.7 to acquired and inherited pain states and the absence of motor, cognitive and cardiac deficits in patients lacking this channel make it an attractive target for the treatment of neuropathic pain. [Abstract]

Duprat F, Lauritzen I, Patel A, Honor� E
The TASK background K(2P) channels: chemo- and nutrient sensors.
Trends Neurosci. 2007 Nov;30(11):573-80.
Specialized chemo- and nutrient-sensing cells share a common electrophysiological mechanism by transducing low O(2), high CO(2) and low glucose stimuli into a compensatory cellular response: the closing of background K(+) channels encoded by the K(2P) subunits. Inhibition of the TASK K(2P) channels by extracellular acidosis leads to an increased excitability of brainstem respiratory neurons. Moreover, hypoxic down-modulation of TASK channels is implicated in the activation of glomus cells in the carotid body. Stimulation of both types of cell leads to an enhanced ventilation and to cardiocirculatory adjustments. Differential modulation of TASK channels by acidosis and high glucose alters excitability of the hypothalamic orexin neurons, which influence arousal, food seeking and breathing. These recent results shed light on the role of TASK channels in sensing physiological stimuli. [Abstract]

Jasanoff A
Bloodless FMRI.
Trends Neurosci. 2007 Nov;30(11):603-10.
Conventional functional magnetic resonance imaging (fMRI) is a blunt tool for studying the nervous system because it measures neural activity only indirectly, by way of hemodynamics and neurovascular coupling. Several alternative, nonhemodynamic functional imaging methods are now being explored. The methods are designed to offer better resolution and neuronal specificity than hemodynamic imaging and, in some cases, might report signals from specific molecules or cell populations. Much progress has concentrated in three areas: diffusion-weighted functional imaging; detection of neuronal electromagnetic fields; and molecular imaging of neural metabolites and signaling species. Here, we review recent developments in these areas. We consider unique advantages and disadvantages of 'bloodless fMRI' approaches, as well as their future prospects as experimental tools in cognitive and systems neuroscience. [Abstract]

Kauffman AS, Clifton DK, Steiner RA
Emerging ideas about kisspeptin- GPR54 signaling in the neuroendocrine regulation of reproduction.
Trends Neurosci. 2007 Oct;30(10):504-11.
Neurons that produce gonadotropin-releasing hormone (GnRH) drive the reproductive axis, but the molecular and cellular mechanisms by which hormonal and environmental signals regulate GnRH secretion remain poorly understood. Kisspeptins are products of the Kiss1 gene, and the interaction of kisspeptin and its receptor GPR54 plays a crucial role in governing the onset of puberty and adult reproductive function. This review discusses the latest ideas about kisspeptin-GPR54 signaling in the neuroendocrine regulation of reproduction, with special emphasis on the role of Kiss1 and kisspeptin in the negative and positive feedback control of gonadotropin secretion by sex steroids, timing of puberty onset, sexual differentiation of the brain and photoperiodic regulation of seasonal reproduction. [Abstract]

Pisani A, Bernardi G, Ding J, Surmeier DJ
Re-emergence of striatal cholinergic interneurons in movement disorders.
Trends Neurosci. 2007 Oct;30(10):545-53.
Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders. [Abstract]

Pocock JM, Kettenmann H
Neurotransmitter receptors on microglia.
Trends Neurosci. 2007 Oct;30(10):527-35.
Microglia are the intrinsic immune cells of the brain and express chemokine and cytokine receptors that interact with the peripheral immune cells. Recent studies have indicated that microglia also respond to the brain's classical signalling substances, the neurotransmitters. Here, we review the evidence for the expression of neurotransmitter receptors on microglia and the consequences of this receptor activation for microglial behaviour. It is evident that neurotransmitters instruct microglia to perform distinct types of responses, such as triggering an inflammatory cascade or acquiring a neuroprotective phenotype. Understanding how microglia respond to different neurotransmitters will thus have important implications for controlling the reactivity of these cells in acute injury, as well as for treating chronic neurodegenerative diseases. [Abstract]

Dub� CM, Brewster AL, Richichi C, Zha Q, Baram TZ
Fever, febrile seizures and epilepsy.
Trends Neurosci. 2007 Oct;30(10):490-6.
Seizures induced by fever (febrile seizures) are the most common type of pathological brain activity in infants and children. These febrile seizures and their potential contribution to the mechanisms of limbic (temporal lobe) epilepsy have been a topic of major clinical and scientific interest. Key questions include the mechanisms by which fever generates seizures, the effects of long febrile seizures on neuronal function and the potential contribution of these seizures to epilepsy. This review builds on recent advances derived from animal models and summarizes our current knowledge of the mechanisms underlying febrile seizures and of changes in neuronal gene expression and function that facilitate the enduring effects of prolonged febrile seizures on neuronal and network excitability. The review also discusses the relevance of these findings to the general mechanisms of epileptogenesis during development and points out gaps in our knowledge, including the relationship of animal models to human febrile seizures and epilepsy. [Abstract]

Lambrechts D, Robberecht W, Carmeliet P
Heterogeneity in motoneuron disease.
Trends Neurosci. 2007 Oct;30(10):536-44.
Recently, mutations in several genes have been identified as primary causes for the degeneration of motoneurons and their axons. Strikingly, mutations in the same genes were associated with clinically different motoneuron syndromes. The identity of these genes also shed light on the mechanisms of motoneuron degeneration and revealed that overlapping motoneuron phenotypes might be caused by heterogeneous molecular mechanisms. Overall, these findings have challenged the diagnostic classification system set by clinical judgement and triggered the notion of heterogeneity in motoneuron disease. It will now be especially relevant to identify the mechanisms and principles that motoneuron diseases have in common, as this will allow us to identify the most relevant therapeutic targets. On the other hand, heterogeneity in motoneuron disease also implies that finding a monotherapy cure for motoneuron disease will be challenging and that pre-clinical testing of therapeutic targets should not be limited to a single animal model. [Abstract]

Fernandez F, Garner CC
Over-inhibition: a model for developmental intellectual disability.
Trends Neurosci. 2007 Oct;30(10):497-503.
Developmental intellectual disability (DID) is a daunting societal problem. Although tremendous progress has been made in defining the genetic causes of DID, therapeutic strategies remain limited. In particular, there is a marked absence of a unified approach to treating cognitive impairments associated with DID. Here, we suggest that the brain in many DID-related disorders is subject to a basic imbalance in neuronal activity, with an increased contribution of inhibition to neural circuits. This over-inhibition, in turn, is predicted to lead to deficits in synaptic plasticity and learning and memory. We further discuss possibilities for pharmacological intervention in DID, focusing on the concept of drug-induced 'therapeutic neuroadaptation' as a means of stably enhancing constitutive circuit excitability and cognition over time. [Abstract]

Benton R
Sensitivity and specificity in Drosophila pheromone perception.
Trends Neurosci. 2007 Oct;30(10):512-9.
How the brain perceives volatile chemicals in the environment to evoke the appropriate behaviour is a fundamental question in sensory neuroscience. The olfactory system of the fruit fly, Drosophila melanogaster, has emerged as a powerful model system to address this problem. Recent analysis of the molecular, neuroanatomical and physiological properties of the olfactory circuits that detect the sex and social aggregation pheromone cis-vaccenyl acetate now provides one of the most comprehensive outlines for the neural basis of odour perception. This review describes these latest advances, discusses what they reveal about where stimulus sensitivity and specificity is encoded in olfactory circuits, and considers future questions. [Abstract]

Yu HH, Lee T
Neuronal temporal identity in post-embryonic Drosophila brain.
Trends Neurosci. 2007 Oct;30(10):520-6.
Understanding how a vast number of neuron types derive from a limited number of neural progenitors remains a major challenge in developmental neurobiology. In the post-embryonic Drosophila brain, specific neuron types derive from specific progenitors at specific times. This suggests involvement of time-dependent cell fate determinants acting as 'temporal codes' along with lineage cues to specify neuronal cell fates. Interestingly, such temporal codes might be provided not only by several regulators acting in sequence, but also by the differential protein levels of the BTB-zinc finger nuclear protein Chinmo. Identifying temporal codes and determining their origins should allow us to elucidate how neuronal diversification occurs through protracted neurogenesis. [Abstract]

Sena E, van der Worp HB, Howells D, Macleod M
How can we improve the pre-clinical development of drugs for stroke?
Trends Neurosci. 2007 Sep;30(9):433-9.
The development of stroke drugs has been characterized by success in animal studies and subsequent failure in clinical trials. Animal studies might have overstated efficacy, or clinical trials might have understated efficacy; in either case we need to better understand the reasons for failure. Techniques borrowed from clinical trials have recently allowed the impact of publication and study-quality biases on published estimates of efficacy in animal experiments to be described. On the basis of these data, we propose minimum standards for the range and quality of pre-clinical animal data. We believe the adoption of these standards will lead to improved effectiveness and efficiency in the selection of drugs for clinical trials in stroke and in the design of those trials. [Abstract]

Leviton A, Gressens P
Neuronal damage accompanies perinatal white-matter damage.
Trends Neurosci. 2007 Sep;30(9):473-8.
Extremely low-gestational-age newborns have a prominently increased risk of brain dysfunctions attributed to white-matter damage, which is thought to result from the vulnerability of the oligodendrocyte. This white-matter damage now appears to be accompanied by cerebral-cortex and deep-gray-matter abnormalities, including excess apoptosis without replacement and the impairment of surviving neurons and resulting interference with synaptogenesis and connectivity. Recent advances in corticogenesis suggest that neurons migrate from the germinative zones through the white matter to the cortex when the white matter is most vulnerable and perhaps is being injured. Advances in developmental neuroscience also suggest that the excitotoxic and inflammatory processes that probably contribute to white-matter damage are also able to damage developing neurons. Together, these advances support the untested hypothesis that white-matter damage in the preterm newborn is accompanied by the death of neurons as they migrate through the dangerous minefield of white matter undergoing injury. [Abstract]

Kampa BM, Letzkus JJ, Stuart GJ
Dendritic mechanisms controlling spike-timing-dependent synaptic plasticity.
Trends Neurosci. 2007 Sep;30(9):456-63.
The ability of neurons to modulate the strength of their synaptic connections has been shown to depend on the relative timing of pre- and postsynaptic action potentials. This form of synaptic plasticity, called spike-timing-dependent plasticity (STDP), has become an attractive model for learning at the single-cell level. Yet, despite its popularity in experimental and theoretical neuroscience, the influence of dendritic mechanisms in the induction of STDP has been largely overlooked. Several recent studies have investigated how active dendritic properties and synapse location within the dendritic tree influence STDP. These studies suggest the existence of learning rules that depend on firing mode and subcellular input location, adding unanticipated complexity to STDP. Here, we propose a new look at STDP that is focused on processing at the postsynaptic site in the dendrites, rather than on spike-timing at the cell body. [Abstract]

Recent Articles in Progress in Neurobiology

Walla P
Olfaction and its dynamic influence on word and face processing: Cross-modal integration.
Prog Neurobiol. 2007 Oct 25;
The article specifies several important aspects related to the sense of smell in vertebrates. The idea that odors exert effects in the human brain though being not consciously perceived is introduced. Functional aspects related to cross-modal sensory interaction between olfaction and vision are highlighted. In particular, studies making use of electrophysiological methods providing high temporal resolution reveal an early processing stage around 300ms and a later stage around 700ms after stimulus onset. The early stage has been associated with subconscious olfactory information processing, whereas the later stage most likely reflects conscious odor perception. Specific interactions are described between olfaction and language and between olfaction and face processing in correlation with both stages of olfactory information processing. A consciously perceived odor can negatively affect language and face processing if these stimuli are presented and associated simultaneously, whereas simultaneous subconscious odor processing has the potential to improve memory formation in other stimulus modalities. Strikingly, the subconscious effect seems not to depend on odor valence. Besides a better understanding of the sense of olfaction itself, these findings on cross-modal integration support the idea that neural representations exist for semantic contents (object meaning) independent from particular sensory modalities. These representations can be referred to as meta representations because the information they contain is derived from a great variety of sensory information integrated into a semantic representation of an object. It is suggested that such meta representations represent the basic units for cognition and that they provide inputs during dreaming. [Abstract]

Song J, Tanouye MA
From bench to drug: Human seizure modeling using Drosophila.
Prog Neurobiol. 2007 Oct 26;
Studies of human seizure disorders have revealed that susceptibility to seizures is greatly influenced by genetic factors. In addition to causing epilepsy, genetic factors can suppress seizures and epileptogenesis. Examination of seizure-suppressor genes is challenging in humans. However, such genes are readily identified and analyzed in a Drosophila animal model of epilepsy. In this article, the epilepsy phenotype of Drosophila seizure-sensitive mutants is reviewed. A novel class of genes called seizure-suppressors is described. Mutations defining suppressors revert the "epilepsy" phenotype of neurological mutants. We conclude this review with particular discussion of a seizure-suppressor gene encoding DNA topoisomerase I (top1). Mutations of top1 are especially effective at reverting the seizure-sensitive phenotype of Drosophila epilepsy mutants. In addition, an unexpected class of anti-epileptic drugs has been identified. These are DNA topoisomerase I inhibitors such as camptothecin and its derivatives; several candidates are comparable or perhaps better than traditional anti-epileptic drugs such as valproate at reducing seizures in Drosophila drug-feeding experiments. [Abstract]

Caldwell HK, Lee HJ, Macbeth AH, Young WS
Vasopressin: Behavioral roles of an "original" neuropeptide.
Prog Neurobiol. 2007 Nov 4;
Vasopressin (Avp) is mainly synthesized in the magnocellular cells of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN) whose axons project to the posterior pituitary. Avp is then released into the blood stream upon appropriate stimulation (e.g., hemorrhage or dehydration) to act at the kidneys and blood vessels. The brain also contains several populations of smaller, parvocellular neurons whose projections remain within the brain. These populations are located within the PVN, bed nucleus of the stria terminalis (BNST), medial amygdala (MeA) and suprachiasmatic nucleus (SCN). Since the 1950s, research examining the roles of Avp in the brain and periphery has intensified. The development of specific agonists and antagonists for Avp receptors has allowed for a better elucidation of its contributions to physiology and behavior. Anatomical, pharmacological and transgenic, including "knockout," animal studies have implicated Avp in the regulation of various social behaviors across species. Avp plays a prominent role in the regulation of aggression, generally of facilitating or promoting it. Affiliation and certain aspects of pair-bonding are also influenced by Avp. Memory, one of the first brain functions of Avp that was investigated, has been implicated especially strongly in social recognition. The roles of Avp in stress, anxiety, and depressive states are areas of active exploration. In this review, we concentrate on the scientific progress that has been made in understanding the role of Avp in regulating these and other behaviors across species. We also discuss the implications for human behavior. [Abstract]

Allain H, Bentu�-Ferrer D, Akwa Y
Disease-modifying drugs and Parkinson's disease.
Prog Neurobiol. 2007 Oct 16;
Symptomatic medications, l-Dopa and dopaminergic agents, remain the only clinically pertinent pharmacological treatment proven effective and available for the large population of patients with Parkinson's disease. The challenge for the pharmaceutical industry is to develop disease-modifying drugs which could arrest, delay or at least oppose the progression of the specific pathogenic processes underlying Parkinson's disease. The purpose of this review, based on recent biological and genetic data to be validated with appropriate animal models, was to re-examine the putative neuroprotective agents in Parkinson's disease and discuss the development of new strategies with the ultimate goal of demonstrating neurocytoprotective activity in this neurodegenerative disease. Since guidelines for research on neurocytoprotective drugs remain to be written, innovation will be the key to success of future clinical trials. It is reasonable to expect that future advances in our understanding of the pathogenic processes of Parkinson's disease will open the way to new perspectives for the treatment of other neurodegenerative diseases. [Abstract]

Florenzano F, Viscomi MT, Amadio S, D'Ambrosi N, Volont� C, Molinari M
Do ATP and NO interact in the CNS?
Prog Neurobiol. 2007 Oct 18;
Enzymatically derived NO and extracellular ATP are receiving greater attention due to their role as messengers in the CNS during different physiological and pathological processes. Ionotropic (P2XR) and metabotropic (P2YR) purinergic receptors mediate ATP effects and are present throughout the body. Particularly P2XR are crucial for brain plasticity mechanisms, and are involved in the pathogenesis of different CNS illnesses. NO does not have a specific receptor and its actions are directly dependent on the production on demand by different nitric oxide synthase isoforms. NO synthesizing enzymes are present virtually in all tissues, and NO influences multifarious physiological and pathological functions. Interestingly, various are the tissue and organs modulated by both ATP and NO, such as the immune, brain and vascular systems. Moreover, direct interactions between purinergic and nitrergic mechanisms outside the CNS are well documented, with several studies also indicating that ATP and NO do participate to the same CNS functions. In the past few years, further experimental evidence supported the physiological and pathological relevance of ATP and NO direct interactions in the CNS. The aim of the present review is to provide an account of the available information on the interplay between purinergic and nitrergic systems, focussing on the CNS. The already established relevance of ATP and NO in different pathological processes would predict that the knowledge of ATP/NO cross-talk mechanisms would support pharmacological approaches toward the development of novel ATP/NO combined pharmacological agents. [Abstract]

Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendon�a A
Adenosine A(2A) receptors and brain injury: Broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation.
Prog Neurobiol. 2007 Dec;83(5):310-31.
This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A(2A) receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A(2A)Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A(2A) receptors in different cellular elements suggest that A(2A) receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A(2A)R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A(2A) receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential. [Abstract]

Knecht S, Ellger T, Levine JA
Obesity in neurobiology.
Prog Neurobiol. 2007 Oct 4;
Obesity reflects an imbalance between energy uptake and expenditure that is mediated by behavior. Obesity is a growing epidemic and a major risk factor for neurobiological diseases like stroke, dementia, intracranial hypertension and sleep disorders. Conversely, obesity can also be induced by neurobiological disorders and drugs. The etiology of obesity is complex and includes biology, behavior and environment. Physicians are faced with the need to manage obesity while strategies for prevention and sustained weight reduction are limited. Present treatment options comprise lifestyle modification, diet, pharmacotherapy and bariatric surgery. Considerable headway has been made into elucidating the neurobiological underpinnings of obesogenic behavior. There is now a growing understanding of the metabolic, hormonal and behavioral circuitries that contribute to the complex and redundant system for energy balance. Changing the net balance of this system to prevent or reduce obesity requires multimodal and long-term interventions. [Abstract]

Talhouk RS, Zeinieh MP, Mikati MA, El-Sabban ME
Gap junctional intercellular communication in hypoxia-ischemia-induced neuronal injury.
Prog Neurobiol. 2007 Oct 10;
Brain hypoxia-ischemia is a relatively common and serious problem in neonates and in adults. Its consequences include long-term histological and behavioral changes and reduction in seizure threshold. Gap junction intercellular communication is pivotal in the spread of hypoxia-ischemia related injury and in mediating its long-term effects. This review provides a comprehensive and critical review of hypoxia-ischemia and hypoxia in the brain and the potential role of gap junctions in the spread of the neuronal injury induced by these insults. It also presents the effects of hypoxia-ischemia and of hypoxia on the state of gap junctions in vitro and in vivo. Understanding the mechanisms involved in gap junction-mediated neuronal injury due to hypoxia will lead to the development of novel therapeutic strategies. [Abstract]

Schwarzschild MA
Adenosine A(2A) antagonists as neurotherapeutics: Crossing the bridge.
Prog Neurobiol. 2007 Dec;83(5):261-2. [Abstract]

Lakshmikuttyamma A, Selvakumar P, Tuchek J, Sharma RK
Myristoyltransferase and calcineurin: Novel molecular therapeutic target for epilepsy.
Prog Neurobiol. 2007 Oct 6;
N-myristoylation is a co-translational, irreversible addition of a fatty acyl moiety to the amino terminus of many eukaryotic cellular proteins. These myristoylated proteins in the cell have diverse biological functions such as signal transduction, cellular transformation and oncogensis. Known myristoylated proteins [Src family kinases, the catalytic subunit of cAMP-dependent protein kinase and calcineurin (CaN)] are either protein kinases or a protein phosphatases which modulate various cellular metabolic processes. Myristoylation is catalyzed by N-myristoyltransferase (NMT) and is recognized to be a widespread and functionally important modification of proteins. The main objective of this review is to focus on the potential role of NMT and CaN in epileptic brain and its involvement in neuronal apoptosis. The findings on the interaction of NMT and CaN with various signaling molecules in epileptic chickens adds to our understanding of the mechanism of CaN signaling in neuronal apoptosis. Understanding the regulation of NMT by specific inhibitors may help us to control the action of this enzyme on its specific substrates and may lead to improvements in the management of various neurological disorders like Alzheimer's disease, ischemia and epilepsy. [Abstract]

Hegd� J
Time course of visual perception: Coarse-to-fine processing and beyond.
Prog Neurobiol. 2007 Sep 29;
Our perception of a visual scene changes rapidly in time, even when the scene itself does not. It is increasingly clear that understanding how the visual percept changes in time is crucial to understanding how we see. We are still far from fully understanding the temporal changes in the visual percept and the neural mechanisms that underlie it. But recently, many disparate lines of evidence are beginning to converge to produce a complex but fuzzy picture of visual temporal dynamics. It is clear, largely from psychophysical studies in humans, that one can get the 'gist' of complex visual scenes within about 150ms after the stimulus onset, even when the stimulus itself is presented as briefly as 10ms or so. It generally takes longer processing, if not longer stimulus presentation, to identify individual objects. It may take even longer for a fuller semantic understanding, or awareness, of the scene to emerge and be encoded in short-term memory. Microelectrode recording studies in monkeys, along with neuroimaging studies mostly in humans, have elucidated many important temporal dynamic phenomena at the level of individual neurons and neuronal populations. Many of the temporal changes at the perceptual and the neural levels can be captured by the multifaceted and somewhat ambiguous concept of coarse-to-fine processing, although it is clear that not all temporal changes can be characterized this way. A more comprehensive, albeit unproven, alternative framework for understanding visual temporal dynamics is to view it as a sequential, Bayesian decision-making process. At each step, the visual system infers the likely nature visual scene by jointly evaluating the available processed image information and prior knowledge about the scene, including prior inferences. Whether the processing proceeds in a coarse-to-fine fashion depends largely on whether the underlying computations are hierarchical or not. Characterizing these inferential steps from the computational, perceptual and neural standpoints will be a key part of future work in this emerging field. [Abstract]

Pan W, Kastin AJ
Tumor necrosis factor and stroke: Role of the blood-brain barrier.
Prog Neurobiol. 2007 Dec;83(6):363-74.
The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor alpha (TNFalpha). TNFalpha crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFalpha, regulation of TNFalpha transport after stroke, and the effects of TNFalpha on stroke preconditioning. TNFalpha can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFalpha may be related to differential regulation of TNFalpha trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFalpha affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke. [Abstract]

Li M, Chen L, Lee DH, Yu LC, Zhang Y
The role of intracellular amyloid beta in Alzheimer's disease.
Prog Neurobiol. 2007 Oct;83(3):131-9.
Extracellular amyloid beta (Abeta) that confers neurotoxicity and modulates synaptic plasticity and memory function has been central to the amyloid hypothesis of Alzheimer's disease (AD) pathology. Like many other misfolded proteins identified in neurodegenerative disorders, Abeta also accumulates inside the AD neurons. This intracellular Abeta affects a variety of cellular physiology from protein degradation, axonal transport, autophagy to apoptosis, further documenting the role of Abeta in AD. Therapeutics targeting intracellular Abeta could be effective treatment for AD. [Abstract]

Lapergue B, Mohammad A, Shuaib A
Endothelial progenitor cells and cerebrovascular diseases.
Prog Neurobiol. 2007 Dec;83(6):349-62.
Identifying factors that may increase the risk of stroke and assessing if treatment of such conditions may lower that risk are important in the management of cerebrovascular disease. Tobacco smoking, poor diet, hypertension and hyperlipidemia remain the major risk factors, and treatment of these conditions has been shown to significantly reduce stroke. In recent years, research has shown that stem cells from a variety of sources can be used as a tool to study and prevent the events that lead to stroke. In this regard, a population of adult stem cells, called endothelial progenitor cells (EPCs), have been identified in peripheral blood and may play an important role in tissue vascularization and endothelium homeostasis in the adult. Most of the studies on EPCs have been carried out on patients with cardiovascular diseases; however, there is emerging evidence which suggests that the introduction or mobilization of EPCs can restore tissue vascularization even after cerebrovascular diseases (CVD), such as ischemic stroke or intracerebral haemorrhage. In this review, we discuss the present level of knowledge about the characteristics of EPCs, their possible therapeutic role in CVD and how they could alter clinical practice in the future. [Abstract]

Buckley NJ
Analysis of transcription, chromatin dynamics and epigenetic changes in neural genes.
Prog Neurobiol. 2007 Nov;83(4):195-210.
The ways in which gene transcription is investigated have undergone radical change since the turn of the millennium. Piece-meal approaches focussed upon model genes have increasingly been complemented by genome-wide approaches that allow interrogation of multiple cohorts of genes or even entire genomes. This sea change has been founded upon the increasing availability of whole genome sequences and the attendant evolution of microarray based discovery platforms. Collectively, these approaches are being used to build a global and dynamic perspective of transcription factor occupancy, co-factor recruitment and epigenetic signature. As yet, few of these approaches have been applied to the study of neuronal gene transcription, but this is set to change. Here, I review these key developments and point to their potential application to the study of transcriptional and epigenetic changes in neurons in health and disease. [Abstract]

Ke Y, Qian ZM
Brain iron metabolism: neurobiology and neurochemistry.
Prog Neurobiol. 2007 Oct;83(3):149-73.
New findings obtained during the past years, especially the discovery of mutations in the genes associated with brain iron metabolism, have provided key insights into the homeostatic mechanisms of brain iron metabolism and the pathological mechanisms responsible for neurodegenerative diseases. The accumulated evidence demonstrates that misregulation in brain iron metabolism is one of the initial causes for neuronal death in some neurodegenerative disorders. The errors in brain iron metabolism found in these disorders have a multifactorial pathogenesis, including genetic and nongenetic factors. The disturbances of iron metabolism might occur at multiple levels, including iron uptake and release, storage, intracellular metabolism and regulation. It is the increased brain iron that triggers a cascade of deleterious events, leading to neuronal death in these diseases. In the article, the recent advances in studies on neurochemistry and neuropathophysiology of brain iron metabolism were reviewed. [Abstract]

Rossini PM, Rossi S, Babiloni C, Polich J
Clinical neurophysiology of aging brain: From normal aging to neurodegeneration.
Prog Neurobiol. 2007 Dec;83(6):375-400.
Physiological brain aging is characterized by a loss of synaptic contacts and neuronal apoptosis that provokes age-dependant decline of sensory processing, motor performance, and cognitive function. Neural redundancy and plastic remodelling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. However, age is the main risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) that impact on cognition. Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including electroencephalography (EEG), event-related potential (ERP), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) can accurately index normal and abnormal brain aging to facilitate non-invasive analysis of cortico-cortical connectivity and neuronal synchronization of firing and coherence of rhythmic oscillations at various frequencies. The present review provides a perspective of these issues by assaying different neurophysiological methods and integrating the results with functional brain imaging findings. It is concluded that discrimination between physiological and pathological brain aging clearly emerges at the group level, with applications at the individual level also suggested. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost and non-invasive evaluation of at-risk populations. Practical implications of the methods are emphasized. [Abstract]

Wang CX, Shuaib A
Critical role of microvasculature basal lamina in ischemic brain injury.
Prog Neurobiol. 2007 Oct;83(3):140-8.
Cerebral vascular system can be divided into two categories: the macrovessels and microvessels. The microvessels consist of arterioles, capillaries and venules. There are three basic components in the microvasculature: endothelial cells, basal lamina and end-feet of astrocytes. The basal lamina is situated between the endothelial cells and the end-feet of astrocytes, and connects these two layers together. Damage to the basal lamina causes the dismantlement of microvascular wall structures, which in turn results in increase of microvascular permeability, hemorrhagic transformation, brain edema and compromise of the microcirculation. The present article reviews microvascular changes during ischemic brain injury, with emphasis on basal lamina damage. [Abstract]

Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA
Role of adenosine A(2A) receptors in parkinsonian motor impairment and l-DOPA-induced motor complications.
Prog Neurobiol. 2007 Dec;83(5):293-309.
Adenosine A(2A) receptors have a unique cellular and regional distribution in the basal ganglia, being particularly concentrated in areas richly innervated by dopamine such as the caudate-putamen and the globus pallidus. Adenosine A(2A) receptors are selectively located on striatopallidal neurons and are capable of forming functional heteromeric complexes with dopamine D(2) and metabotropic glutamate mGlu5 receptors. Based on the unique cellular and regional distribution of this receptor and in line with data showing that A(2A) receptor antagonists improve motor symptoms in animal models of Parkinson's disease (PD) and in initial clinical trials, A(2A) receptor antagonists have emerged as an attractive non-dopaminergic target to improve the motor deficits that characterize PD. Experimental data have also shown that A(2A) receptor antagonists do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review provides an updated summary of results reported in the literature concerning the biochemical characteristics and basal ganglia distribution of A(2A) receptors. We subsequently aim to examine the effects of adenosine A(2A) antagonists in rodent and primate models of PD and of l-DOPA-induced dyskinesia. Finally, concluding remarks are made on post-mortem human brains and on the translation of adenosine A(2A) receptor antagonists in the treatment of PD. [Abstract]

Saxena S, Caroni P
Mechanisms of axon degeneration: from development to disease.
Prog Neurobiol. 2007 Oct;83(3):174-91.
Axon degeneration is an active, tightly controlled and versatile process of axon segment self-destruction. Although not involving cell death, it resembles apoptosis in its logics. It involves three distinct steps: induction of competence in specific neurons, triggering of degeneration at defined axon segments of competent neurons, and rapid fragmentation and removal of the segments. The mechanisms that initiate degeneration are specific to individual settings, but the final pathway of pruning is shared; it involves microtubule disassembly, axon swellings, axon fragmentation, and removal of the remnants by locally recruited phagocytes. The tight regulatory properties of axon degeneration distinguish it from passive loss phenomena, and confer significance to processes that involve it. Axon degeneration has prominent roles in development, upon lesions and in disease. In development, it couples the progressive specification of neurons and circuits to the removal of defined axon branches. Competence might involve transcriptional switches, and local triggering can involve axon guidance molecules and synaptic activity patterns. Lesion-induced Wallerian degeneration is inhibited in the presence of Wld(S) fusion protein in neurons; it involves early local, and later, distal degeneration. It has recently become clear that like in other settings, axon degeneration in disease is a rapid and specific process, which should not be confused with a variety of disease-related pathologies. Elucidating the specific mechanisms that initiate axon degeneration should open up new avenues to investigate principles of circuit assembly and plasticity, to uncover mechanisms of disease progression, and to identify ways of protecting synapses and axons in disease. [Abstract]

Fredholm BB, Chern Y, Franco R, Sitkovsky M
Aspects of the general biology of adenosine A(2A) signaling.
Prog Neurobiol. 2007 Dec;83(5):263-76.
Many of our current hopes of finding better ways to treat Parkinson's disease or to stop its progression rely on studies of adenosine A(2A) receptors in the brain. Yet any drug targeting central receptors will also potentially affect receptors in other sites. Furthermore, several fundamental aspects of adenosine receptor biology must be taken into account. For these reasons the "Targeting adenosine A2A receptors in Parkinson's disease and other CNS disorders" meeting in Boston included selected aspects of the general biology of adenosine A(2A) receptor signaling. Some of the presentations from this part of the meeting are summarized in this first chapter. As will be apparent to the reader, these different parts do not form an integrated whole, but they do indicate areas the organizers felt might illuminate remaining questions regarding the roles of adenosine A(2A) receptors. The contributors to this part of the meeting have summarized some of the key questions below. [Abstract]

Cattaneo E
Chromatin dysfunction in Huntington's disease.
Prog Neurobiol. 2007 Nov;83(4):193-4. [Abstract]

Briand LA, Gritton H, Howe WM, Young DA, Sarter M
Modulators in concert for cognition: modulator interactions in the prefrontal cortex.
Prog Neurobiol. 2007 Oct;83(2):69-91.
Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems. [Abstract]

Garc�a-L�pez P, Garc�a-Mar�n V, Freire M
The discovery of dendritic spines by Cajal in 1888 and its relevance in the present neuroscience.
Prog Neurobiol. 2007 Oct;83(2):110-30.
The year 2006 marks the centenary of the Nobel Prize for Physiology or Medicine awarded to Santiago Ram�n y Cajal and Camilo Golgi, "in recognition of their work on the structure of the nervous system". Their discoveries are keys to understanding the present neuroscience, for instance, the discovery of dendritic spines. Cajal discovered dendritic spines in 1888 with the Golgi method, although other contemporary scientists thought that they were silver precipitates. Dendritic spines were demonstrated definitively as real structures by Cajal with the Methylene Blue in 1896. Many of the observations of Cajal and other contemporary scientists about dendritic spines are active fields of research of present neuroscience, for instance, their morphology, distribution, density, development and function. This article will deal with the main contributions of Cajal and other contemporary scientists about dendritic spines. We will analyse their contributions from the historical and present point of view. In addition, we will show high quality images of Cajal's original preparations and drawings related with this discovery. [Abstract]

Antonelli T, Fuxe K, Tomasini MC, Mazzoni E, Agnati LF, Tanganelli S, Ferraro L
Neurotensin receptor mechanisms and its modulation of glutamate transmission in the brain: relevance for neurodegenerative diseases and their treatment.
Prog Neurobiol. 2007 Oct;83(2):92-109.
The extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular N-methyl-D-aspartate (NMDA) receptors, have been postulated to contribute to the neuronal cell death associated with chronic neurodegenerative disorders such as Parkinson's disease. Findings are reviewed indicating that the tridecaptide neurotensin (NT) via activation of NT receptor subtype 1 (NTS1) promotes and reinforces endogenous glutamate signalling in discrete brain regions. The increase of striatal, nigral and cortical glutamate outflow by NT and the enhancement of NMDA receptor function by a NTS1/NMDA interaction that involves the activation of protein kinase C may favour the depolarization of NTS1 containing neurons and the entry of calcium. These results strengthen the hypothesis that NT may be involved in the amplification of glutamate-induced neurotoxicity in mesencephalic dopamine and cortical neurons. The mechanisms involved may include also antagonistic NTS1/D2 interactions in the cortico-striatal glutamate terminals and in the nigral DA cell bodies and dendrites as well as in the nigro-striatal DA terminals. The possible increase in NT levels in the basal ganglia under pathological conditions leading to the NTS1 enhancement of glutamate signalling may contribute to the neurodegeneration of the nigro-striatal dopaminergic neurons found in Parkinson's disease, especially in view of the high density of NTS1 receptors in these neurons. The use of selective NTS1 antagonists together with conventional drug treatments could provide a novel therapeutic approach for treatment of Parkinson's disease. [Abstract]

T�r�k TL
Electrogenic Na+/Ca2+-exchange of nerve and muscle cells.
Prog Neurobiol. 2007 Aug;82(6):287-347.
The plasma membrane Na(+)/Ca(2+)-exchanger is a bi-directional electrogenic (3Na(+):1Ca(2+)) and voltage-sensitive ion transport mechanism, which is mainly responsible for Ca(2+)-extrusion. The Na(+)-gradient, required for normal mode operation, is created by the Na(+)-pump, which is also electrogenic (3Na(+):2K(+)) and voltage-sensitive. The Na(+)/Ca(2+)-exchanger operational modes are very similar to those of the Na(+)-pump, except that the uncoupled flux (Na(+)-influx or -efflux?) is missing. The reversal potential of the exchanger is around -40 mV; therefore, during the upstroke of the AP it is probably transiently activated, leading to Ca(2+)-influx. The Na(+)/Ca(2+)-exchange is regulated by transported and non-transported external and internal cations, and shows ATP(i)-, pH- and temperature-dependence. The main problem in determining the role of Na(+)/Ca(2+)-exchange in excitation-secretion/contraction coupling is the lack of specific (mode-selective) blockers. During recent years, evidence has been accumulated for co-localisation of the Na(+)-pump, and the Na(+)/Ca(2+)-exchanger and their possible functional interaction in the "restricted" or "fuzzy space." In cardiac failure, the Na(+)-pump is down-regulated, while the exchanger is up-regulated. If the exchanger is working in normal mode (Ca(2+)-extrusion) during most of the cardiac cycle, upregulation of the exchanger may result in SR Ca(2+)-store depletion and further impairment in contractility. If so, a normal mode selective Na(+)/Ca(2+)-exchange inhibitor would be useful therapy for decompensation, and unlike CGs would not increase internal Na(+). In peripheral sympathetic nerves, pre-synaptic alpha(2)-receptors may regulate not only the VSCCs but possibly the reverse Na(+)/Ca(2+)-exchange as well. [Abstract]

Mandel S, Amit T, Bar-Am O, Youdim MB
Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents.
Prog Neurobiol. 2007 Aug;82(6):348-60.
Considering the multi-etiological character of Alzheimer's disease (AD), the current pharmacological approaches using drugs oriented towards a single molecular target possess limited ability to modify the course of the disease and thus, offer a partial benefit to the patient. In line with this concept, novel strategies include the use of a cocktail of several drugs and/or the development of a single molecule, possessing two or more active neuroprotective-neurorescue moieties that simultaneously manipulate multiple targets involved in AD pathology. A consistent observation in AD is a dysregulation of metal ions (Fe(2+), Cu(2+) and Zn(2+)) homeostasis and consequential induction of oxidative stress, associated with beta-amyloid aggregation and neurite plaque formation. In particular, iron has been demonstrated to modulate the Alzheimer's amyloid precursor holo-protein expression by a pathway similar to that of ferritin L-and H-mRNA translation through iron-responsive elements in their 5'UTRs. This review will discuss two separate scenarios concerning multiple therapy targets in AD, sharing in common the implementation of iron chelation activity: (i) novel multimodal brain-permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities; (ii) natural plant polyphenols (flavonoids), such as green tea epigallocatechin gallate (EGCG) and curcumin, reported to have access to the brain and to possess multifunctional activities, such as metal chelation-radical scavenging, anti-inflammation and neuroprotection. [Abstract]

Berger A, Kofman O, Livneh U, Henik A
Multidisciplinary perspectives on attention and the development of self-regulation.
Prog Neurobiol. 2007 Aug;82(5):256-86.
During infancy and early childhood, children develop their ability to regulate their own emotions and behavior. This development of self-regulatory mechanisms has been considered to be the crucial link between genetic predisposition, early experience, and later adult functioning in society. This paper brings together the updated empirical findings related to the role of attention and the maturation of brain frontal areas in self-regulation. It reviews viewpoints and evidence of disciplines such as developmental psychology, cognitive neuroscience, social psychology, and neurobiology. It examines the causes of individual differences in self-regulation and the effects of those differences on the social and academic functioning of the individual. The consequences of failure in self-regulation are illustrated by focusing on the attention deficit/hyperactivity disorder (ADHD), including a detailed review of the animal models related to this disorder. Finally, some initial evidence suggesting the possibility of fostering self-regulation through training of attention is presented. [Abstract]

Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferr� S
Adenosine A(2A) receptors and basal ganglia physiology.
Prog Neurobiol. 2007 Dec;83(5):277-92.
Adenosine A(2A) receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A(2A) receptor tightly interacts structurally and functionally with the dopamine D(2) receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A(2A) and D(2) receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A(2A)/D(2) receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A(2A) receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A(1) receptors. Therefore, A(2A) receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D(2) receptors, group I metabotropic mGlu(5) glutamate receptors and cannabinoid CB(1) receptors, and by triggering the cAMP-protein kinase A signaling cascade. [Abstract]

Brown TM, Piggins HD
Electrophysiology of the suprachiasmatic circadian clock.
Prog Neurobiol. 2007 Aug;82(5):229-55.
In mammals, an internal timekeeping mechanism located in the suprachiasmatic nuclei (SCN) orchestrates a diverse array of neuroendocrine and physiological parameters to anticipate the cyclical environmental fluctuations that occur every solar day. Electrophysiological recording techniques have proved invaluable in shaping our understanding of how this endogenous clock becomes synchronized to salient environmental cues and appropriately coordinates the timing of a multitude of physiological rhythms in other areas of the brain and body. In this review we discuss the pioneering studies that have shaped our understanding of how this biological pacemaker functions, from input to output. Further, we highlight insights from new studies indicating that, more than just reflecting its oscillatory output, electrical activity within individual clock cells is a vital part of SCN clockwork itself. [Abstract]

Recent Articles in Behavioural Brain Research

Moy SS, Nadler JJ, Poe MD, Nonneman RJ, Young NB, Koller BH, Crawley JN, Duncan GE, Bodfish JW
Development of a mouse test for repetitive, restricted behaviors: Relevance to autism.
Behav Brain Res. 2007 Nov 4; .
Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T(+)tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1(neo/neo) mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T(+)tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T(+)tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1(neo/neo) mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1(neo/neo) mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test. [Abstract]

Hernandez G, Rajabi H, Stewart J, Arvanitogiannis A, Shizgal P
Dopamine tone increases similarly during predictable and unpredictable administration of rewarding brain stimulation at short inter-train intervals.
Behav Brain Res. 2007 Nov 7;
Unpredicted rewards, but not predicted ones, trigger strong phasic changes in the firing rates of midbrain dopamine (DA). In contrast, neurochemical measurements of DA tone have failed to reveal an influence of reward predictability. However, the subjects of the neurochemical experiments were asked to predict reward onset over longer intervals (12s, on average) than the subjects of the electrophysiological studies (typically, 2s). Thus, the contrasting effects of reward predictability could reflect the difference in the duration of the interval separating the predictor from the reward rather than a difference in the influence of reward predictability on phasic and tonic DA signaling. This hypothesis was tested in rats receiving trains of rewarding electrical brain stimulation with either a predictable or unpredictable onset. The mean inter-train interval was 1.5s, a value close to the 2-s CS-US interval that has been used in electrophysiological studies demonstrating the dependence of phasic DA responses on reward predictability. Despite the shortened inter-train interval, the time courses of the observed stimulation-induced elevations in DA levels were very similar, regardless of whether train onset was predictable. This finding is consistent with the idea that tonic DA signaling is insensitive to the predictability of rewards. [Abstract]

Silasi G, Hamilton DA, Kolb B
Social instability blocks functional restitution following motor cortex stroke in rats.
Behav Brain Res. 2007 Nov 4;
Social interactions have previously been shown to influence stroke outcome. In the current experiment we investigated the effects of a changing social environment on anatomical and behavioral recovery following motor cortex stroke in rats. Adult rats were trained on the Whishaw single pellet reaching task prior to receiving a devascularizing stroke lesion of the motor cortex. During the post-stroke testing period half of the rats were exposed to a form of social experience that has previously been shown to stimulate synaptic plasticity in frontal cortex circuitry, whereas the remaining rats were housed in pairs, in standard cages. At the end of the experiment the brains were processed for Golgi-Cox staining and dendritic length was measured in layer V of the intact forelimb motor area, layer III of Zilles' area Cg3 and layer II/III of Zilles' area AID. Social experience was found to completely block the normal spontaneous behavioural restitution in the lesion animals. Anatomically, whereas social experience selectively increased dendritic length in AID in rats that had not undergone behavioral training or the stroke procedure, this was not seen in the lesion animals, as the lesion alone produced an increase in dendritic length in both AID and Cg3. The findings are discussed in terms of the role of social experiences, including stress, on spontaneous plasticity that occurs following unilateral motor cortex stroke, and the effectiveness of inducing synaptic plasticity to promote behavioural recovery. [Abstract]

Lehner M, Taracha E, Sk�rzewska A, Turzy?ska D, Sobolewska A, Maciejak P, Szyndler J, Hamed A, Bidzi?ski A, Wis?owska-Stanek A, P?a?nik A
Expression of c-Fos and CRF in the brains of rats differing in the strength of a fear response.
Behav Brain Res. 2007 Nov 4;
The aim of the study was to examine the neurochemical background of differences in the individual responses to conditioned aversive stimuli, using the strength of a rat conditioned freezing response (the contextual fear test), as a discriminating variable. It was shown that low responders (LR), i.e. rats with duration of a freezing response one standard error, or more, below the mean value, had a higher activity of the M2 cortical area, and the median raphe nucleus (c-Fox expression), in comparison to the high responders (HR), i.e. rats with the duration of a freezing response one standard error, or more, above the mean value. These animals had also stronger 5-HT- and CRF-related immunostaining in the M2 area, and increased concentration of GABA in the basolateral nucleus of amygdala (in vivo microdialysis). The LR group vocalized more during test session in the aversive band, and had higher serum levels of corticosterone, examined 10min after test session. It was shown that different natural patterns of responding to conditioned aversive stimuli are associated with different involvement of brain structures and with dissimilar neurochemical mechanisms. [Abstract]

Ruocco LA, Viggiano D, Pignatelli M, Iannaccone T, Rimoli MG, Melisi D, Curcio A, De Lucia S, Carboni E, Carnevale UA, de Caprariis P, Sadile AG
Galactosilated dopamine increases attention without reducing activity in C57BL/6 mice.
Behav Brain Res. 2007 Oct 13;
Different strategies can be used to carry dopamine into the brain such as l-Dopa precursors or galactosilated form of DA (GAL-DA). The aim of this study was to investigate weather GAL-DA would reduce hyperactivity and increase non-selective attention (NSA) in a mouse model of attention deficit hyperactivity disorder (ADHD), as, i.e. C57BL/6 as did in NHE rats. Here we report that GAL-DA increases NSA in a special novelty in C57BL/6 mice. They received a single i.p. injection of GAL-DA (10mg/kg or 100mg/kg) or equimolar galactose vehicle. Another mouse strain the Swiss albino was introduced as inbred control group. Three hours after last injection mice were tested in a L�t-maze for 30-min. Behaviour was analyzed for horizontal (traveled distance) and vertical activity (orienting frequency and scanning durations) which shares cognitive and non-cognitive nature, respectively. Ten milligram per kilograms of GAL-DA, increases scanning duration in C57BL/6 mice. Thus a low dose of GAL-DA increases NSA without reducing hyperactivity in this mouse model of ADHD. [Abstract]

Choi YH, Li C, Hartzell DL, Little DE, Della-Fera MA, Baile CA
ICV leptin effects on spontaneous physical activity and feeding behavior in rats.
Behav Brain Res. 2007 Nov 1;
Although leptin causes negative energy balance by reducing food intake and increasing energy expenditure, the effect of leptin on spontaneous physical activity (SPA) is not clearly established. To test the hypothesis that leptin enhances SPA in rats, male Sprague-Dawley rats were injected intracerebroventricularly (ICV) with either 10mug of leptin or artificial cerebrospinal fluid (aCSF) before dark onset (12:00h) once daily for 5 successive days. The rats were individually housed in behavioral monitoring cages to measure feeding behavior and SPA throughout the study. Both groups had a diurnal pattern of SPA being low during the light period and high during the dark period. Specifically, there were two peaks of SPA during the dark period, with the first peak taking place around the dark onset and the second occurring approximately 6h towards the light onset. Leptin treatment resulted in a significant increase in SPA whether or not it was expressed in terms of light-dark, daily or diurnal basis. Increased SPA was consistently observed throughout the entire 5-day study in spite of the fact that the rats were consistently eating less and losing body weight. With reduction in weight of fat pads and increase in apoptosis of fat pads but no change in body temperature, leptin decreased size, duration and number of meals without altering eating rate, thereby increasing satiety. Our data show that increased activity is a key determinant in negative energy balance induced by leptin, which cannot be accounted for solely by the leptin-induced food intake reduction. [Abstract]

M�ndez M, M�ndez-L�pez M, L�pez L, Aller MA, Arias J, Cimadevilla JM, Arias JL
Spatial memory alterations in three models of hepatic encephalopathy.
Behav Brain Res. 2007 Oct 26;
A behavioural evaluation was carried out on three chronic models of hepatic encephalopathy: two models of type B HE, portacaval shunt (PCS) and portal hypertension (PH) and one of type C HE with cirrhosis and portal hypertension from thioacetamide intoxication (TAA). The tasks selected cover a wide range of behaviours related to: locomotion (rotarod-accelerod test), anxiety (open field and elevated plus maze) and memory (Morris water maze). The results indicate that neither locomotor activity nor anxiety was affected in our models, in comparison with their respective controls. However, this is not the case for the mnesic tasks. Hence, the PCS and TAA groups displayed a severe alteration in spatial reference memory and cannot correctly perform the Morris maze task, while this alteration is less severe in the PH group. On the contrary, the PH group revealed a deficit in spatial working memory, like the TAA group, but this does not occur in subjects with PCS. These results reveal a double dissociation in spatial reference memory and spatial working memory between the PCS and PH groups, which would be of great interest to study about cerebral causes and substrates of the alterations accompanying HE. [Abstract]

Renteria AF, Silbaugh BC, Tolentino JC, Gilbert PE
Age-related changes in conditioned flavor preference in rats.
Behav Brain Res. 2007 Oct 25;
Age-related changes have been documented in regions of the brain shown to process reward information. However, few studies have examined the effects of aging on associative memory for reward. The present study tested 7- and 24-month-old rats on a conditioned flavor preference task. Half of the rats in each age group received an unsweetened grape-flavored solution (CS-) on odd-numbered days and a sweetened cherry-flavored solution (CS+) on even-numbered days. The remaining rats in each age group received a sweetened grape-flavored solution (CS+) on odd-numbered days and an unsweetened cherry-flavored solution (CS-) on even-numbered days. During the acquisition phase of testing, the designated solution (CS+ or CS-) was presented to each rat for 15min daily across six consecutive days. On the preference phase, each rat received unsweetened cherry and unsweetened grape-flavored solutions simultaneously for 15min daily across four consecutive days. The 7-month-old rats showed a significant preference for the flavor that was previously sweetened during the acquisition phase (CS+) compared to the previously unsweetened solution (CS-) when the two unsweetened solutions were presented simultaneously during the preference phase of testing. In contrast, the 24-month-old rats did not show a preference and consumed roughly equal amounts of the previously sweetened (CS+) and unsweetened (CS-) solutions. Thus, the data suggest that the ability to form flavor-reward associations declines with increasing age, resulting in impaired conditioned flavor preference. [Abstract]

Santucci AC, Cortes C, Bettica A, Cortes F
Chronic ethanol consumption in rats produces residual increases in anxiety 4 months after withdrawal.
Behav Brain Res. 2007 Oct 22;
The present study investigated the long-term effects of ethanol consumption in rats. Subjects were maintained on either an ethanol (alcohol) (2.7-6.7%, v/v) or an isocaloric liquid control diet for 26 consecutive days (M=13.7g/kg/day). Testing for working memory was conducted in a Morris water maze (2 trials/day for 8 days) and commenced after either a short (19 days) or long (120 days) abstinence period. This was followed by assessment of 72h retention of passive avoidance. Animals were killed either 41 (short abstinence) or 152 days (long abstinence) post-ethanol and their brains stained with cresyl violet. Assessments of dorsal-ventral and medial-lateral cortical vertices were measured in sections derived from eight coronal planes extending +4.20 to -4.16mm from Bregma. Results indicated that subjects in the ethanol/long abstinence group exhibited increased state anxiety due to their propensity to be thigmotaxtic (i.e., wall-hugging) in the water maze. Unfortunately, such a swim pattern precluded assessment of working memory in our subjects. No evidence of ethanol-induced memory decrements were observed on retention of passive avoidance. There was some evidence that animals in the ethanol/long abstinent group suffered cortical thinning and slight compression of the CA1 layer within the hippocampus, although age might have contributed to the former effect. It was concluded that chronic ethanol consumption increases anxiety even after an extended period of withdrawal and may conspire with age to affect cortical integrity. [Abstract]

Cachard-Chastel M, Devers S, Sicsic S, Langlois M, Lezoualc'h F, Gardier AM, Belzung C
Prucalopride and donepezil act synergistically to reverse scopolamine-induced memory deficit in C57Bl/6j mice.
Behav Brain Res. 2007 Oct 18;
It is known that 5-HT(4) receptor agonists increase sAPPalpha levels in the cortex and hippocampus of mice as well as in a model of Alzheimer's disease (AD). As sAPPalpha is thought to have pro-mnesic properties, we assessed whether its increase induces cognitive improvement in a spatial memory task and whether it reverses a scopolamine-induced memory deficit. Mice treated or not treated with scopolamine were trained in the Morris water maze for 3 days. Before the probe test, they received an injection of either a 5-HT(4) receptor agonist (prucalopride or RS 67333), or an acetylcholinesterase inhibitor (donepezil), or both drugs. As expected, scopolamine decreased performance, an effect that was not reversed by the drugs tested when injected alone. However, prucalopride (5mgkg(-1), s.c.) acted synergistically with donepezil (0.75mgkg(-1), s.c.) to counteract completely scopolamine-induced amnesia. Western blot analysis of tissue homogenates in the cortex and hippocampus shows that sAPPalpha levels did not differ between saline- and scopolamine-treated mice. Furthermore, a region-dependent drug action was observed since the scopolamine-treated mice display a tendency to increase sAPPalpha levels in the hippocampus after donepezil or in the cortex after prucalopride. Our results suggest that a combined treatment with a 5-HT(4) receptor agonist with an acetylcholinesterase inhibitor has beneficial effects on memory in mice. Moreover, it seems to enhance sAPPalpha levels in two brain regions highly affected in AD. Thus, a drug polytherapy could be interesting not only to enhance cognitive performance and decrease drawbacks but also to get the best action in each brain region. [Abstract]

Ennaceur A, Michalikova S, van Rensburg R, Chazot PL
Are benzodiazepines really anxiolytic? Evidence from a 3D maze spatial navigation task.
Behav Brain Res. 2007 Nov 1;
The effects of diazepam and chlordiazepoxide were assessed in a 3D maze which is a modification of an 8-arm radial maze. Each arm of the maze is attached to a bridge radiating from a central platform. Animals exposed for the first time to the maze do not venture beyond the line that separate a bridge from an arm. The prime criteria set for an anxiolytic effect is whether mice would increase the frequency of entries onto arms and increase arm/bridge entries ratio. C57 mice readily cross the line on first exposure and make more than 8 arm visits onto arms on second exposure, while other strains (CD-1 and Balb/c) hold back and rarely cross the line on first exposure and require more sessions to make more than 8 arm entries. An anxiolytic drug is expected to encourage intermediate (CD-1) and high (Balb/c) anxiety mice to adventure onto the arms of the maze and make more visits to the arms to comparable levels seen with low anxiety c57 mice. In the present report, administration of different doses of diazepam (0.625, 1.25, 2.5 and 5mgkg(-1) i.p.) and chlordiazepoxide (5, 10 and 15mgkg(-1) i.p.) did not reduce anxiety in animals, with the lowest dose of diazepam increasing motor activity in Balb/c and increasing anxiety in c57 mice while the highest doses of both diazepam (2.5 and 5mgkg(-1) i.p.) and chlordiazepoxide (15mgkg(-1) i.p.) induced mild sedation. Our results raise some concerns about the methodological foundations in the current assessment of anxiety and anxiolytic compounds both in animal and human studies. [Abstract]

Shipman SL, Astur RS
Factors affecting the hippocampal BOLD response during spatial memory.
Behav Brain Res. 2007 Oct 22;
The hippocampus has long been implicated in spatial memory, from work in rodents to imaging and brain lesion studies in humans. However, recent evidence has pointed to the recruitment of areas outside the hippocampus proper on spatial memory tasks, including the parahippocampal gyrus and precuneus, possibly suggesting a more focused role for the hippocampus proper. In this study, a virtual version of the standard rodent spatial memory assessment, the Morris water task, has been employed during fMRI to investigate the differential involvement of these distinct brain areas. Twenty-eight healthy participants completed a block designed version of the virtual Morris water task (vMWT) which consisted of three conditions: (1) a hippocampal dependent condition during which the participants were forced to use distal room cues in the virtual environment to navigate to a hidden platform; (2) a non-hippocampal dependent condition during which participants were to navigate to a visible platform; (3) a fixation period. Activations of the BOLD signal were evident in the hidden condition as compared to the visible condition in the parahippocampal gyrus, precuneus, and fusiform when analyzed using to a blocked analysis. Moreover, this blocked analysis revealed increases in the right hippocampal BOLD signal during fixation. However, when hidden trials were compared to visible trials using a post hoc event-related analysis focused on the beginning of each trial, activations of the right hippocampus are evident. These results support the theory that extra-hippocampal structures contribute to spatial memory behavior and identify a temporally specific involvement of the hippocampus. Furthermore, they substantiate previous results reporting hippocampal BOLD increases during fixation. [Abstract]

Charron C, Fr�chette S, Proulx G, Plamondon H
In vivo administration of corticotropin-releasing hormone at remote intervals following ischemia enhances CA1 neuronal survival and recovery of spatial memory impairments: A role for opioid receptors.
Behav Brain Res. 2007 Nov 4;
The contribution of corticotropin-releasing hormone (CRH) in the modulation of ischemia-induced cell death in vivo remains unclear. We characterized the impact of pre-ischemic administration of CRH (0, 0.1, 1, 5mug, i.c.v., 15min prior to vessel occlusion) on neuronal damage following global ischemia in rats. The injection of 5mug CRH led to a 37% increase in CA1 neuronal survival compared to vehicle-treated ischemic animals, while pre-treatment with alpha-helical CRH (9-41) abolished this neuronal protection. A second objective aimed to determine whether CRH protection is maintained over weeks when the peptide is administered at remote time intervals following ischemia. Compared to vehicle-treated ischemic animals, administration of CRH 8h following global ischemia led to a 61% increase in CA1 neuronal survival observed 30 days post-ischemia. Neuronal protection translated into significant improvement of ischemia-induced spatial memory deficits in the radial maze. Finally, our findings demonstrated that selective blockade of kappa- and delta-opioid receptors (using nor-binaltorphimine and naltrindole, respectively) prior to CRH administration significantly reduced CA1 neuronal protection. These findings represent the first demonstration of enhanced neuronal survival following in vivo CRH administration in a global model of ischemia in rats. They also support the idea that CRH-induced neuroprotection involves opioid receptors activation. [Abstract]

da Cunha IC, Lopes AP, Steffens SM, Ferraz A, Vargas JC, de Lima TC, Marino Neto J, Paschoalini MA, Faria MS
The microinjection of AMPA receptor antagonist into the accumbens shell, but not into the accumbens core, induces anxiolysis in an animal model of anxiety.
Behav Brain Res. 2007 Nov 1;
This study investigated the effect of the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) microinjected into the core and shell sub-regions of the accumbens nucleus (Acb), on the level of fear/anxiety and emotional learning, in female rats submitted to the elevated plus-maze (EPM), an animal model of anxiety. Bilateral microinjections of DNQX (330 and 660ng) into the Acb shell (AP, +1.08 to +2.16) induced an anxiolytic-like effect in relation to rats microinjected with vehicle, since there was an increased percentage of entries in the open arms of the maze. The 660ng DNQX microinjection into the Acb shell also increased the percentage of entries into the open arms in relation to 660ng DNQX microinjection into the Acb core. Prior DNQX microinjections in both core and shell sub-regions of the Acb failed to impair the emotional learning, since the animals exhibited an increase of the open arm avoidance on EPM Trial 2 in relation to EPM trial1. DNQX microinjections into both sub-regions of the Acb did not change the number of entries into the enclosed arms, either in the EPM Trial 1 or in the EPM Trial 2, which indicates an absence of drug-induced locomotor impairment. Similarly, DNQX microinjections into both sub-regions of the Acb failed to alter the total arm entries, rearing, grooming and head-dipping frequency. The anxiolytic-like effect induced by DNQX suggests that the AMPA receptor in the Acb shell, but not in the Acb core, may underlie anxiety regulation in the EPM. [Abstract]

Speedie N, Gerlai R
Alarm substance induced behavioral responses in zebrafish (Danio rerio).
Behav Brain Res. 2007 Nov 4;
Zebrafish (zebra danio) are becoming increasingly popular in behavioral neuroscience and behavior genetics. This small vertebrate may be utilized in modeling human brain disorders. One of the major neuropsychiatric conditions still not well understood is abnormally increased fear and anxiety. Zebrafish may be an appropriate organism with which these human diseases can be modeled and their biological mechanisms investigated. Predator induced anxiety paradigms have been suggested as useful methods in translational research. Shoaling fish, such as zebrafish, are known to respond to alarm substances with antipredatory or alarm reactions. However, these responses are not well characterized in zebrafish. In the current paper, we investigate the behavioral responses of zebrafish elicited by its alarm substance. Using observation-based as well as video-tracking aided behavior quantification methods we demonstrate significant alarm substance-induced behavioral changes that are independent of the presence of a predatory fish stimulus. The results suggest that, once refined, the use of alarm substance with zebrafish will allow the development of high throughput behavioral paradigms for drug and mutation screening aimed at the analysis of the biological mechanisms of fear in vertebrates. [Abstract]

Harooni HE, Naghdi N, Sepehri H, Rohani AH
Intra hippocampal injection of testosterone impaired acquisition, consolidation and retrieval of inhibitory avoidance learning and memory in adult male rats.
Behav Brain Res. 2007 Oct 25;
The hippocampus is essentially involved in learning and memory, and is known to be a target for androgen actions. Androgen receptors are densely expressed in CA1 of rat hippocampus, and mediate the effects of testosterone (T) on learning and memory. T depletion or administration can modulate neural function and cognitive performance. We conducted series of experiments to further investigate the effect of castration or intra hippocampal injection of T on acquisition, consolidation and retrieval of inhibitory avoidance learning and memory. Male adult rats were bilaterally cannulated into CA1 of hippocampus, and then received T (1, 10, 20, 40 and 80mug/0.5mul/side) or vehicle (DMSO), 30min before training, immediately after training and 30min before retrieval in inhibitory avoidance task. Castration was made by gonadectomy of male rats and behavioral tests performed 4 weeks later. Our results showed that gonadectomy of male rats did not influence performance on inhibitory avoidance task, as compared to sham-operated rats. We have also found that pre-training, post-training and pre-retrieval intra CA1 injections of T significantly decreased step-through latencies in inhibitory avoidance learning at doses 1 and 80, 20, and 20 and 40mug/0.5mul/side, respectively. The data suggest that intra CA1 administration of T could impair learning and memory acquisition, consolidation and retrieval, while systemic androgen's depletion have no effect on memory, in inhibitory avoidance task. [Abstract]

Suchan B, Melde C, Herzog H, H�mberg V, Seitz RJ
Activation differences in observation of hand movements for imitation or velocity judgement.
Behav Brain Res. 2007 Oct 30;
We aimed to investigate the brain areas engaged in observation of hand movements with the intention of imitation or judging movement velocity. Both processes reflect different analytic approaches in movement observation. We were interested if these two processes can be distinguished or share common activation foci. Twelve healthy, right-handed volunteers were required to observe video clips of hand gestures and of object related grasping movements while the regional cerebral blood flow was measured using positron emission tomography. The subjects were instructed either to imitate the actions or to judge the velocity of the observed movements after scanning. Action observation with the instruction to judge movement velocity engaged bilaterally the temporo-occipital junction and adjacent visual cortical areas. In contrast, observation with the instruction to imitate them afterwards, yielded large activation clusters covering the left parietal and premotor cortex. Both contrasts demonstrated activation in the inferior frontal cortex, however, on opposite sides. Results suggest that movement observation with the goal of imitation activated specific areas of the parietal cortex in the dominant hemisphere probably related to programming of the movement kinematics. In contrast, observation with the goal to characterize the velocity of the finger movements activated the ventral visual pathways. Thus, movement observation recruits non-overlapping cortical networks, depending on the information attended to which are characterised by a dorsal ventral dissociation. [Abstract]

K�ks S, Fernandes C, Kurrikoff K, Vasar E, Schalkwyk LC
Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice.
Behav Brain Res. 2007 Oct 26;
The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity. [Abstract]

Brand�o ML, Zanoveli JM, Ruiz-Martinez RC, Oliveira LC, Landeira-Fernandez J
Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety.
Behav Brain Res. 2007 Oct 25;
Freezing defined as the complete absence of body movements is a normal response of animals to unavoidable fear stimuli. The present review presents a series of evidence relating different defensive patterns with specific anxiety disorders. There are at least four different kinds of freezing with specific neural substrates. The immobility induced by stimulation of the ventral column of the periaqueductal gray (vPAG) has been considered a quiescence characteristic of the recovery component of defense-recuperative processes. There is an isomorphism between freezing response to contextual stimuli paired with electrical shocks and generalized anxiety disorder. Besides, two types of freezing emerge with the electrical stimulation of the dorsal aspects of the periaqueductal gray (dPAG): the dPAG-evoked freezing and the dPAG post-stimulation freezing. Evidence is presented in support of the hypothesis that whereas dPAG-evoked freezing would serve as a model of panic attacks, the dPAG post-stimulation freezing appears to be a model of panic disorder. It is also proposed that conditioned freezing plus dPAG electrical stimulation might also mimic panic disorder with agoraphobia. A model of serotoninergic modulation through on- and off-cells of the defense reaction generated in the dPAG is also presented. The understanding of how the periaqueductal gray generates and elaborates different types of freezing is of relevance for our better knowledge of distinct types of anxiety such as panic disorder or generalized anxiety disorder. [Abstract]

Yang LM, Hu B, Xia YH, Zhang BL, Zhao H
Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus.
Behav Brain Res. 2007 Nov 1;
The dorsal raphe nucleus (DRN)-serotonin (5-HT) system plays a key role in stress-related psychiatric disorders such as anxiety and depression. The habenular nucleus (Hb) is closely connected with the DRN both morphologically and functionally. Here, we used two types of depressive animal models by exposing rats to chronic mild stress (CMS) and by chronically administering the tricyclic antidepressant clomipramine (CLI) in the rat during the neonatal state of life to produce adult depressed rats. We investigated the effects of lateral habenular nucleus (LHb) lesions on the behavioral response and on the level of 5-HT in DRN in the depressed rats. Forced-swimming test (FST) showed that the immobility time decreased, and the climbing time increased after lesioning LHb of depressed rats. Microdialysis results indicated that the 5-HT level in DRN in depressed rats was lower than that of the control group. Lesion of the LHb was followed by an increased 5-HT turnover in the DRN. Our results suggested that the lesion of the LHb could improve the behavioral response of the depressed rats and the 5-HT level of the DRN increased by LHb lesions could be involved in the effects. [Abstract]

Kanagal SG, Muir GD
The differential effects of cervical and thoracic dorsal funiculus lesions in rats.
Behav Brain Res. 2007 Oct 22;
The purpose of this research was to compare the locomotor abilities of rats with cervical dorsal spinal funicular (DF) lesions to those of rats with the same lesion at the mid-thoracic level. The dorsal funiculus, consisting of ascending sensory fibers and the main component of the corticospinal tract, was transected either at spinal level C2 or at T8. We examined limb force generation and limb timing and coordination during overground locomotion, as well as foot placement errors during locomotion over a horizontal ladder. At 6 weeks post-surgery, bilateral lesions of the cervical DF caused subtle but persistent changes in the generation of ground reaction forces and limb timing during overground locomotion, and caused persistent forelimb, but not hindlimb, errors during ladder crossing. In contrast, the same lesion at the mid-thoracic level did not affect overground locomotion and caused only minor forelimb and hindlimb errors during ladder walking at 2 weeks post-lesion which recovered to pre-surgical levels by 6 weeks post-lesion. DF lesions at cervical vs. thoracic levels thus have differential effects on locomotor abilities in rats. We compare these results with previous work and suggest that the differential response to DF transection might be related to both functional distinctions between the fore- and hindlimbs and to anatomical differences in the dorsal funiculi at different spinal levels. These findings have implications for the mechanisms of recovery as well as the types of behavioural tests which can be practically used to measure functional changes in different lesion models. [Abstract]

Chen CY, Muggleton NG, Juan CH, Tzeng OJ, Hung DL
Time pressure leads to inhibitory control deficits in impulsive violent offenders.
Behav Brain Res. 2007 Oct 22;
Impulsive violent criminal behavior is often ascribed to problems with behavioral control. Such behavior could be a consequence of stronger pre-potent responses or a failure of inhibitory control. A countermanding task which allows dissociation of these two processes was used to examine whether impulsive violent offenders were found to exhibit impaired inhibitory control. An experiment with a time restriction on responding was performed to effectively limit the ability of the subjects to strategically control their error rate. The results showed that the performance of the impulsive violent offenders was only impaired in the time pressure condition. These findings suggest that impulsive violent behavior may be linked to abnormal modulation of the frontal cortical areas, areas thought to be involved in response inhibition by negative feedback or emotional responses, rather than frontal dysfunction per se. [Abstract]

Snigdha S, Neill JC
Efficacy of antipsychotics to reverse phencyclidine-induced social interaction deficits in female rats-A preliminary investigation.
Behav Brain Res. 2007 Oct 22;
Sub-chronic phencyclidine (PCP) treatment mimics certain aspects of schizophrenia symptomology in rats. However, there is a marked lack of attempts to model negative symptomology such as social behaviour deficits in female rats. This study was conducted to assess whether sub-chronic PCP treatment produces social interaction deficits in female rats and to ascertain if these deficits can be reversed by either typical (haloperidol) or atypical (clozapine and ziprasidone) antipsychotics. [Abstract]

Montag C, Hartmann P, Merz M, Burk C, Reuter M
D(2) receptor density and prepulse inhibition in humans: Negative findings from a molecular genetic approach.
Behav Brain Res. 2007 Oct 13;
There is plenty of evidence from schizophrenia research and psychopharmacological experiments showing the influence of the dopaminergic neurotransmission on the prepulse inhibition (PPI). A lot of insights into the underlying neural mechanisms of the PPI have been gained from animal models, which are in need to be validated in humans. Due to new technological advances, findings from psychopharmacological challenge tests can now be verified with techniques from molecular genetics which provide an elegant non-invasive approach. To close the gap between animal research and research in humans in this field a molecular genetic approach was applied to investigate the neural mechanisms of the PPI in healthy subjects. In N=96 female participants recruited out of a sample of N=800 subjects according to their genotypes we tested the association between the DRD2 Taq Ia and the COMT Val158Met polymorphisms, and the magnitude of the eye-blink reflex in an acoustic PPI paradigm. Neither significant influences of both dopaminergic single nucleotide polymorphisms nor an epistasis effect could be detected. Although findings do not support the hypothesis that two of the most prominent dopaminergic candidate loci (DRD2 Taq Ia and COMT Val158Met) effect PPI the study does not exclude the relevance of the dopaminergic system in general. Further molecular genetic studies investigating other variants on dopaminergic genes have to be conducted. [Abstract]

Antoniou K, Papathanasiou G, Papalexi E, Hyphantis T, Nomikos GG, Spyraki C, Papadopoulou-Daifoti Z
Individual responses to novelty are associated with differences in behavioral and neurochemical profiles.
Behav Brain Res. 2007 Oct 22;
Experimental animals can be differentiated on the basis of their horizontal or vertical activity to high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with behavioral and neurobiological differences in a number of experimental procedures used for studying sensitivity to psychostimulants, anxiety, depression, and cognitive function. In the present study, we differentiated the rats to HR and LR based on their vertical activity upon exposure to a novel environment. Additionally, we ascertained whether HR and LR rats differ in a battery of tests such as passive avoidance (PA), object recognition (OR), and the water-maze (WM) that provide indices for cognitive function and the forced swim test (FST), an animal model of affective responsivity and antidepressant-like activity. Potential differences in neurochemical indices between the two phenotypes were also examined. HR rats displayed impaired non-spatial object recognition memory, but enhanced spatial performance, as compared to LR rats. FST induced "depressive-like" symptoms in both phenotypes that were differently manifested in HR versus LR rats. Neurochemical findings revealed distinct differences in serotonergic and dopaminergic activity in the striatum and the prefrontal cortex of HR as compared to LR rats. The above results show that HR and LR rats exhibit important differences in a battery of tests related to cognitive performance or affective responsivity, which may be associated with differences in certain neurobiological parameters. [Abstract]

Nishijo H, Hori E, Tazumi T, Ono T
Neural correlates to both emotion and cognitive functions in the monkey amygdala.
Behav Brain Res. 2007 Oct 22;
Recent lesion and non-invasive studies identify the medial temporal lobe, including the amygdala, not only with emotion but also with working memory in relation to the prefrontal cortex. In the present study, amygdalar neuronal activity was recorded from monkeys during performance of discrimination tasks that led to presentation of emotion-related (rewarding or aversive) stimuli. The task had three phases: (1) discrimination (visual, auditory), (2) operant response (bar pressing) and (3) ingestion (reward) or avoidance (aversion). These neurons were further analyzed by a short-term memory task, delayed pair comparison (DPC) using colored lamps. Of 585 amygdalar neurons, 107 responded primarily to single sensory stimulation (40 vision related, 26 audition related, 41 ingestion related), 117 to multimodal stimulation (multimodal) and 14 responded selectively to only one item (selective). Of 417 neurons tested by the DPC, 122 responded in one or more phases. Of these 122 neurons, 10.7% responded in the delay period. These delay-responsive neurons also responded to various objects with positive and negative affective significance. These results suggest that amygdalar neurons are not specifically related to working memory, as are those in the inferotemporal and prefrontal cortices, but are related to more general non-specific functions or processes such as arousal or attention during the cognitive tasks. A functional role of the amygdala in working memory is discussed in terms of recent non-invasive studies suggesting a functional coupling between the amygdala and prefrontal cortex. [Abstract]

Hirnstein M, Hausmann M, G�nt�rk�n O
The evolutionary origins of functional cerebral asymmetries in humans: Does lateralization enhance parallel processing?
Behav Brain Res. 2007 Sep 25;
Functional cerebral asymmetries (FCAs) are a fundamental principle of brain organization in many species. However, little is known about why they have evolved. Since FCAs are such a widespread phenomenon they seem to constitute an evolutionary selective advantage. According to a prominent hypothesis, an asymmetric brain should be associated with advantages in parallel processing, i.e. doing two tasks simultaneously. The strong version of this hypothesis implies that lateralized, instantaneous and complementary tasks are performed more efficiently with a highly lateralized brain. Using a visual half-field procedure, we wanted to test this strong version of the parallel-processing hypothesis in humans. Thirty-two participants (17 women, 15 men) were investigated. First, we assessed the degree of lateralization in a face/non-face and a word/non-word discrimination task favouring the right and left hemisphere, respectively. Based on a median split, subjects were divided into a rather symmetric and a rather asymmetric group. Then, all participants completed both tasks simultaneously. The results revealed that the rather symmetrically organized participants outperformed asymmetric participants in accuracy and response times. Hence, the strong version of the parallel-processing hypothesis has to be revised. [Abstract]

Barbelivien A, Billy E, Lazarus C, Kelche C, Majchrzak M
Rats with different profiles of impulsive choice behavior exhibit differences in responses to caffeine and d-amphetamine and in medial prefrontal cortex 5-HT utilization.
Behav Brain Res. 2007 Sep 21;
This study investigated if sub-populations of rats characterized by their basal level of impulsivity (BLI) in a delayed-reinforcement task, displayed differences in the functioning of neurotransmitter systems modulating impulsive choice behavior. For this, the effects of various doses of caffeine and d-amphetamine were investigated in three sub-populations of rats displaying pronounced differences in their impulsive choice behavior and their post-mortem serotonergic and dopaminergic functions were assessed. Caffeine and d-amphetamine reduce impulsive choice behavior only in the Medium BLI sub-population. Dopamine utilization was similar in the three sub-populations, but serotonin utilization was lower in the prefrontal cortex of the Medium and Very high BLI sub-populations as compared to the low BLI one. These results suggest that anti-impulsive effects of caffeine and d-amphetamine are dependent on the BLI of rats and that a low serotonergic function in the prefrontal cortex may be a trait marker of impulsivity evaluated by impulsive choice behavior. [Abstract]

da Costa Ferreira G, Schuck PF, Viegas CM, Tonin A, Ribeiro CA, Pettenuzzo LF, Pereira LO, Netto CA, Wajner M
Chronic early postnatal glutaric acid administration causes cognitive deficits in the water maze.
Behav Brain Res. 2007 Oct 11;
Glutaric acidemia type I (GA I) is an autosomal recessive metabolic disorder caused by glutaryl-CoA dehydrogenase deficiency leading to predominant accumulation of glutaric acid (GA), and to a lesser extent of 3-hydroxyglutaric acid (3HG) in body fluids and tissues. The clinical manifestations of GA I are predominantly neurological. Although the pathophysiological mechanisms responsible for the brain damage of this disease are virtually unknown, they are thought to be due to the neurotoxic actions of GA and 3HG. Therefore, in the present work we investigated whether chronic exposure of GA (5mumolg of body weight(-1), twice per day), the major metabolite accumulating in GA I, during early development (from the 5th to the 28th day of life) could alter the cognitive performance of adult rats in the Morris water maze, open field and elevated plus maze tasks. Control rats were treated with saline in the same volumes. GA administration provoked an impairment of spatial performance in the water maze since adult rats pretreated with GA were not able to remember the previous location of the platform spending significantly less time in the training quadrant. In contrast, GA chronic administration did not affect rat performance in the open field and elevated plus maze tasks, indicating that motor activity and anxiety was not changed by GA. The results provide evidence that early chronic GA treatment induces long-lasting spatial behavioral deficit. [Abstract]

Tallett AJ, Blundell JE, Rodgers RJ
Behaviourally-selective hypophagic effects of naloxone in non-deprived male rats presented with palatable food.
Behav Brain Res. 2007 Oct 13;
Endogenous opioids have long been implicated in mechanisms of appetite control. A significant strand in the evidence base has been the hypophagic action of broad-spectrum opioid receptor antagonists (such as naloxone) in opiate-na�ve animals. However, while much has been learned about sites of action, underlying receptor mechanisms and the role of taste hedonics, surprisingly little is known about the behavioural selectivity of naloxone-induced hypophagia. As such, two experiments employed detailed video analysis to profile the behavioural effects of naloxone (Experiment 1: 1.0-5.0mg/kg; Experiment 2: 0.01-1.0mg/kg) in non-deprived male rats during 1h free-feeding tests with palatable mash. Results confirmed that, at doses >/=1.0mg/kg, naloxone consistently suppresses food consumption and feeding behaviour but, congruent with its short biological half-life, had no carryover effects on post-treatment weight gain. Crucially, the anorectic doses of naloxone did not alter the time taken to find food or to commence feeding, the time spent feeding in the initial phase of testing, or the rate at which food was consumed. Furthermore, they neither interfered with non-ingestive components of the behavioural repertoire (e.g. locomotion, rearing) nor did they disrupt the normal structure of feeding behaviour (the behavioural satiety sequence, BSS). Rather, the principal effect of naloxone was to produce a shift to the left in (i.e. accelerate) the BSS. Findings are discussed in relation to the role of (mu) opioid receptor mechanisms in taste hedonics and the likelihood of a naloxone-induced reduction in the orosensory reward that would normally accompany/follow the ingestion of palatable food. [Abstract]

Recent Articles in Current Opinion in Neurobiology

Martini L, Whistler JL
The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence.
Curr Opin Neurobiol. 2007 Dec 6;
Following activation, most G protein coupled receptors undergo regulation by a cascade of events that promote receptor desensitization and endocytosis. Following endocytosis, receptors can then be recycled to the plasma membrane, retained in an intracellular compartment, or targeted for degradation. For receptors that are recycled, like the mu opioid receptor (MOR), endocytosis serves as the first step toward resensitizing receptors. For receptors that are degraded, endocytosis serves as the first step toward receptor downregulation. Thus, for receptors like the MOR, the desensitization-endocytosis-resensitization cycle serves as a rapid and dynamic means to titrate signaling through the receptor. However, not all agonist ligands at the MOR promote the same degree of receptor desensitization and endocytosis. For example, the endogenous peptide ligands at the MOR induce rapid desensitization, endocytosis, and recycling. By contrast, morphine induces only weak or partial desensitization and little to no endocytosis. As a consequence, signal transduction promoted by morphine is less dynamic than that induced by endogenous ligands as well as other opioid agonists that promote endocytosis. The resulting imbalance of desensitization-endocytosis-resensitization has at least two consequences: (1) in cell types where morphine induces desensitization but not endocytosis and/or resensitization, desensitization is protracted; (2) in cell types where morphine induces neither desensitization nor endocytosis, prolonged signaling through the receptor leads to multiple cellular adaptations downstream of receptor-G protein coupling. Both protracted desensitization and adaptive cellular changes probably contribute to the pronounced in vivo tolerance and dependence that occur with chronic morphine treatment. As a consequence, facilitating receptor endocytosis, using either genetic or pharmacological approaches, can restore the balance of signaling through the receptor and affect the development of tolerance and dependence. [Abstract]

Tervo D, Karpova AY
Rapidly inducible, genetically targeted inactivation of neural and synaptic activity in vivo.
Curr Opin Neurobiol. 2007 Nov 28;
Inducible and reversible perturbation of the activity of selected neurons in vivo is critical to understanding the dynamics of brain circuits. Several genetically encoded systems for rapid inducible neuronal silencing have been developed in the past few years offering an arsenal of tools for in vivo experiments. Some systems are based on ion-channels or pumps, others on G protein coupled receptors, and yet others on modified presynaptic proteins. Inducers range from light to small molecules to peptides. This diversity results in differences in the various parameters that may determine the applicability of each tool to a particular biological question. Although further development would be beneficial, the current silencing tool kit already provides the ability to make specific perturbations of circuit function in behaving animals. [Abstract]

Barth AL
Visualizing circuits and systems using transgenic reporters of neural activity.
Curr Opin Neurobiol. 2007 Nov 23;
Genetically encoded sensors of neural activity enable visualization of circuit-level function in the central nervous system. Although our understanding of the molecular events that regulate neuronal firing, synaptic function, and plasticity has expanded rapidly over the past 15 years, an appreciation for how cellular changes are functionally integrated at the circuit level has lagged. A new generation of tools that employ fluorescent sensors of neural activity promises unique opportunities to bridge the gap between cellular level and system level analysis. This review will focus on genetically encoded sensors. A primary advantage of these indicators is that they can be nonselectively introduced to large populations of cells using either transgenic-mediated or viral-mediated approaches. This ability removes the nontrivial obstacles of how to get chemical indicators into cells of interest, a problem that has dogged investigators who have been interested in mapping neural function in the intact CNS. Five different types of approaches and their relative utility will be reviewed here: first, reporters of immediate-early gene (IEG) activation using promoters such as c-fos and arc; second, voltage-based sensors, such as GFP-coupled Na(+) and K(+) channels; third, Cl(-)-based sensors; fourth, Ca(2+)-based sensors, such as Camgaroo and the troponin-based TN-L15; and fifth, pH-based sensors, which have been particularly useful for examining synaptic activity of highly convergent afferents in sensory systems in vivo. Particular attention will be paid to reporters of IEG expression, because these tools employ the built-in threshold function that occurs with activation of gene expression, provoking new experimental questions by expanding the timescale of analysis for circuit-level and system-level functional mapping. [Abstract]

Luan H, White BH
Combinatorial methods for refined neuronal gene targeting.
Curr Opin Neurobiol. 2007 Nov 15;
Methods for the selective and reproducible expression of genetically encoded tools in targeted subsets of cells are required to facilitate studies of neuronal development, connectivity, and function in living animals. In the absence of techniques for synthesizing promoters that target defined cell groups, current methods exploit the regulatory elements of endogenous genes to achieve specificity of transgene expression. However, single promoters often have expression patterns too broad to pinpoint the functional roles of specific neurons. In this review, we describe emerging combinatorial techniques that make transgene expression contingent not upon a single promoter, but upon two or more promoters. Although only a few such techniques are currently available, recent developments promise rapid growth in this area in the coming years. [Abstract]

Gogolla N, Galimberti I, Caroni P
Structural plasticity of axon terminals in the adult.
Curr Opin Neurobiol. 2007 Oct 18;
There is now conclusive evidence for widespread ongoing structural plasticity of presynaptic boutons and axon side-branches in the adult brain. The plasticity complements that of postsynaptic spines, but axonal plasticity samples larger volumes of neuropil, and has a larger impact on circuit remodeling. Axons from distinct neurons exhibit unique ratios of stable (t(1/2)>9 months) and dynamic (t(1/2) 5-20 days) boutons, which persist as spatially intermingled subgroups along terminal arbors. In addition, phases of side-branch dynamics mediate larger scale remodeling guided by synaptogenesis. The plasticity is most pronounced during critical periods; its patterns and outcome are controlled by Hebbian mechanisms and intrinsic neuronal factors. Novel experience, skill learning, life-style, and age can persistently modify local circuit structure through axonal structural plasticity. [Abstract]

Forman MS, Trojanowski JQ, Lee VM
TDP-43: a novel neurodegenerative proteinopathy.
Curr Opin Neurobiol. 2007 Oct 11;
Over the past decade, it has become clear that there is a significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and ALS provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxy-terminal fragments in affected brain regions. The normal nuclear expression of TDP-43 is also reduced leading to the hypothesis that sequestration of TDP-43 in pathological inclusions contributes to disease pathogenesis. Thus, TDP-43 is the newest member of the growing list of neurodegenerative proteinopathies, but unique in that it lacks features of brain amyloidosis. [Abstract]

Imai T, Sakano H
Roles of odorant receptors in projecting axons in the mouse olfactory system.
Curr Opin Neurobiol. 2007 Oct 10;
In the mouse olfactory epithelium, there are about ten million olfactory sensory neurons, each expressing a single type of odorant receptor out of approximately 1000. Olfactory sensory neurons expressing the same odorant receptor converge their axons to a specific set of glomeruli on the olfactory bulb. How odorant receptors play an instructive role in the projection of axons to the olfactory bulb has been one of the major issues of developmental neurobiology. Recent studies revealed previously overlooked roles of odorant receptor-derived cAMP signals in the axonal projection of olfactory sensory neurons; the levels of cAMP and neuronal activity appear to determine the expression levels of axon guidance/sorting molecules and thereby direct the axonal projection of olfactory sensory neurons. These findings provide new insights as to how peripheral inputs instruct neuronal circuit formation in the mammalian brain. [Abstract]

Gao FB
Molecular and cellular mechanisms of dendritic morphogenesis.
Curr Opin Neurobiol. 2007 Oct 12;
Dendrites exhibit unique cell type-specific branching patterns and targeting specificity that are crucially important for neuronal function and connectivity. Recent evidence indicates that highly complex transcriptional regulatory networks dictate various aspects of dendritic outgrowth, branching, and routing. In addition to other intrinsic molecular pathways such as membrane protein trafficking, interactions between neighboring dendritic branches also contribute to the final specification of dendritic morphology. Nonredundant coverage by dendrites of same type of neurons, known as tiling, requires the actions of the Tricornered/Furry (Sax-1/Sax-2) signaling pathway. However, the dendrites of a neuron do not crossover each other, a process called self-avoidance that is mediated by Down's syndrome cell adhesion molecule (Dscam). Those exciting findings have enhanced significantly our understanding of dendritic morphogenesis and revealed the magnitude of complexity in the underlying molecular regulatory networks. [Abstract]

Knust E
Photoreceptor morphogenesis and retinal degeneration: lessons from Drosophila.
Curr Opin Neurobiol. 2007 Oct 12;
Cells exhibit an amazingly wide range of different forms, and in most cases the shape of a cell is crucial for performing its specific function(s). But how does a cell obtain its particular shape during development, how can the shape be adapted to different environmental conditions, and what are the consequences if morphogenesis is impaired? An ideal cell type to study these questions is the photoreceptor cell, a photosensitive cell present in most metazoa, highly specialised to transform the energy from the light into a visual response. In the last few years, studies in the Drosophila eye have led to a considerable increase in understanding of the genetic control of photoreceptor morphogenesis; lessons, which may apply to other cell types as well. Most of the genes involved have been conserved during evolution, and mutations in several of them result in retinal degeneration, both in flies and humans. This makes the fly eye an attractive model to unravel the genetic, molecular and cell biological basis of the mechanisms that prevent retinal dystrophies. [Abstract]

Simons M, Trotter J
Wrapping it up: the cell biology of myelination.
Curr Opin Neurobiol. 2007 Oct 6;
During nervous system development, oligodendroglia in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) synthesise large amounts of specific proteins and lipids to generate myelin, a specialised membrane that spirally ensheathes axons and facilitates fast conduction of the action potential. Myelination is initiated after glial processes have attached to the axon and polarisation of the plasma membrane has been triggered. Myelin assembly is a multi-step process that occurs in spatially distinct regions of the cell. We propose that assembly of myelin proteins and lipids starts during their transport through the biosynthetic pathway and continues at the plasma membrane aided by myelin-basic protein (MBP). These sequential processes create the special lipid and protein composition necessary for myelin to perform its insulating function during nerve conduction. [Abstract]

Zador A, Mombaerts P
Neuronal circuitry and population activity.
Curr Opin Neurobiol. 2007 Aug;17(4):395-6. [Abstract]

Conway BR, Livingstone MS
Perspectives on science and art.
Curr Opin Neurobiol. 2007 Aug;17(4):476-82.
Artists try to understand how we see, sometimes explicitly exploring rules of perspective or color, visual illusions, or iconography, and conversely, scientists who study vision sometimes address the perceptual questions and discoveries raised by the works of art, as we do here. [Abstract]

Ohki K, Reid RC
Specificity and randomness in the visual cortex.
Curr Opin Neurobiol. 2007 Aug;17(4):401-7.
Research on the functional anatomy of visual cortical circuits has recently zoomed in from the macroscopic level to the microscopic. High-resolution functional imaging has revealed that the functional architecture of orientation maps in higher mammals is built with single-cell precision. By contrast, orientation selectivity in rodents is dispersed on visual cortex in a salt-and-pepper fashion, despite highly tuned visual responses. Recent studies of synaptic physiology indicate that there are disjoint subnetworks of interconnected cells in the rodent visual cortex. These intermingled subnetworks, described in vitro, may relate to the intermingled ensembles of cells tuned to different orientations, described in vivo. This hypothesis may soon be tested with new anatomic techniques that promise to reveal the detailed wiring diagram of cortical circuits. [Abstract]

Wark B, Lundstrom BN, Fairhall A
Sensory adaptation.
Curr Opin Neurobiol. 2007 Aug;17(4):423-9.
Adaptation occurs in a variety of forms in all sensory systems, motivating the question: what is its purpose? A productive approach has been to hypothesize that adaptation helps neural systems to efficiently encode stimuli whose statistics vary in time. To encode efficiently, a neural system must change its coding strategy, or computation, as the distribution of stimuli changes. Information theoretic methods allow this efficient coding hypothesis to be tested quantitatively. Empirically, adaptive processes occur over a wide range of timescales. On short timescales, underlying mechanisms include the contribution of intrinsic nonlinearities. Over longer timescales, adaptation is often power-law-like, implying the coexistence of multiple timescales in a single adaptive process. Models demonstrate that this can result from mechanisms within a single neuron. [Abstract]

Fritz JB, Elhilali M, David SV, Shamma SA
Auditory attention--focusing the searchlight on sound.
Curr Opin Neurobiol. 2007 Aug;17(4):437-55.
Some fifty years after the first physiological studies of auditory attention, the field is now ripening, with exciting recent insights into the psychophysics, psychology, and neural basis of auditory attention. Current research seeks to unravel the complex interactions of pre-attentive and attentive processing of the acoustic scene, the role of auditory attention in mediating receptive-field plasticity in both auditory spatial and auditory feature processing, the contrasts and parallels between auditory and visual attention pathways and mechanisms, the interplay of bottom-up and top-down attentional mechanisms, the influential role of attention, goals, and expectations in shaping auditory processing, and the orchestration of diverse attentional effects at multiple levels from the cochlea to the cortex. [Abstract]

Dahmen JC, King AJ
Learning to hear: plasticity of auditory cortical processing.
Curr Opin Neurobiol. 2007 Aug;17(4):456-64.
Sensory experience and auditory cortex plasticity are intimately related. This relationship is most striking during infancy when changes in sensory input can have profound effects on the functional organization of the developing cortex. But a considerable degree of plasticity is retained throughout life, as demonstrated by the cortical reorganization that follows damage to the sensory periphery or by the more controversial changes in response properties that are thought to accompany perceptual learning. Recent studies in the auditory system have revealed the remarkably adaptive nature of sensory processing and provided important insights into the way in which cortical circuits are shaped by experience and learning. [Abstract]

Nirenberg SH, Victor JD
Analyzing the activity of large populations of neurons: how tractable is the problem?
Curr Opin Neurobiol. 2007 Aug;17(4):397-400.
Understanding how the brain performs computations requires understanding neuronal firing patterns at successive levels of processing-a daunting and seemingly intractable task. Two recent studies have made dramatic progress on this problem by showing how its dimensionality can be reduced. Using the retina as a model system, they demonstrated that multineuronal firing patterns can be predicted by pairwise interactions. [Abstract]

Nobre A, Correa A, Coull J
The hazards of time.
Curr Opin Neurobiol. 2007 Aug;17(4):465-70.
Temporal expectations are continuously formed and updated, and interact with expectations about other relevant attributes of events, in order to optimise our interaction with unfolding sensory stimulation. In this paper, we will highlight some evidence revealing the pervasive effects of temporal expectations in modulating perception and action, and reflect on the current state of understanding about their underlying neural systems and mechanisms. [Abstract]

Zufall F, Leinders-Zufall T
Mammalian pheromone sensing.
Curr Opin Neurobiol. 2007 Aug;17(4):483-9.
The traditional distinction that the mammalian main olfactory system recognizes general odor molecules and the accessory (vomeronasal) system detects pheromones is no longer valid. The emerging picture is that both systems have considerable overlap in terms of the chemosignals they detect and the effects that they mediate. Recent investigations have discovered large families of pheromonal signals together with a rich variety of specific receptor systems and nasal detection pathways. Selective genetic targeting of these subsystems should help to unravel their biological role in pheromone-mediated behavioral responses. [Abstract]

Ren T, Gillespie PG
A mechanism for active hearing.
Curr Opin Neurobiol. 2007 Aug;17(4):498-503.
The remarkable sensitivity, frequency selectivity, and nonlinearity of the cochlea have been attributed to the putative 'cochlear amplifier', which consumes metabolic energy to amplify the cochlear mechanical response to sounds. Recent studies have demonstrated that outer hair cells actively generate force using somatic electromotility and active hair-bundle motion. However, the expected power gain of the cochlear amplifier has not been demonstrated experimentally, and the measured location of cochlear nonlinearity is inconsistent with the predicted location of the cochlear amplifier. We instead propose a 'cochlear transformer' mechanism to interpret cochlear performance. [Abstract]

Sherman SM
The thalamus is more than just a relay.
Curr Opin Neurobiol. 2007 Aug;17(4):417-22.
The lateral geniculate nucleus and pulvinar are examples of two different types of relay: the former is a first order relay, transmitting information from a subcortical source (retina), while the latter is mostly a higher order relay, transmitting information from layer 5 of one cortical area to another cortical area. First and higher order thalamic relays can also be recognized for much of the rest of thalamus, and most of thalamus seems to be comprised of higher order relays. Higher order relays seem especially important to general corticocortical communication, and this challenges and extends the conventional view that such communication is based on direct corticocortical connections. [Abstract]

Bandell M, Macpherson LJ, Patapoutian A
From chills to chilis: mechanisms for thermosensation and chemesthesis via thermoTRPs.
Curr Opin Neurobiol. 2007 Aug;17(4):490-7.
Six highly temperature-sensitive ion channels of the transient receptor potential (TRP) family have been implicated to mediate temperature sensation. These channels, expressed in sensory neurons innervating the skin or the skin itself, are active at specific temperatures ranging from noxious cold to burning heat. In addition to temperature sensation thermoTRPs are the receptors of a growing number of environmental chemicals (chemesthesis). Recent studies have provided some striking new insights into the molecular mechanism of thermal and chemical activation of these biological thermometers. [Abstract]

Kreiman G
Single unit approaches to human vision and memory.
Curr Opin Neurobiol. 2007 Aug;17(4):471-5.
Research on the visual system focuses on using electrophysiology, pharmacology and other invasive tools in animal models. Non-invasive tools such as scalp electroencephalography and imaging allow examining humans but show a much lower spatial and/or temporal resolution. Under special clinical conditions, it is possible to monitor single-unit activity in humans when invasive procedures are required due to particular pathological conditions including epilepsy and Parkinson's disease. We review our knowledge about the visual system and visual memories in the human brain at the single neuron level. The properties of the human brain seem to be broadly compatible with the knowledge derived from animal models. The possibility of examining high-resolution brain activity in conscious human subjects allows investigators to ask novel questions that are challenging to address in animal models. [Abstract]

Brecht M
Barrel cortex and whisker-mediated behaviors.
Curr Opin Neurobiol. 2007 Aug;17(4):408-16.
Neural networks of the rodent barrel cortex are particularly tractable for developing a quantitative understanding of response transformations in a cortical column. A column in barrel cortex consists of approximately 10 compartments. Two thalamic input pathways, a sensory lemniscal one and sensorimotor paralemniscal one, are transformed to approximately 7 population outputs, each with distinct spatiotemporal response characteristics. Granular and supragranular layers are sites of segregated processing in lemniscal and paralemniscal pathways, whereas infragranular layers are sites of intracolumnar, lemniscal/paralemniscal integration. Individual thalamocortical connections are relatively weak, and a considerable fraction of thalamocortical afferents contributes to each sensory response. Intracortically, relatively few but strong synaptic connections contribute to sensory responses, and responses are rapidly terminated by inhibition. Overall cortical population activity is very low. Whiskers mediate a wide range of behaviors and many natural tactile behaviors occur very rapidly. Vibrissal object recognition can be size invariant and motion invariant and is based on the tactile 'Gestaltwahrnehmung' of shape. [Abstract]

Benda J, Gollisch T, Machens CK, Herz AV
From response to stimulus: adaptive sampling in sensory physiology.
Curr Opin Neurobiol. 2007 Aug;17(4):430-6.
Sensory systems extract behaviorally relevant information from a continuous stream of complex high-dimensional input signals. Understanding the detailed dynamics and precise neural code, even of a single neuron, is therefore a non-trivial task. Automated closed-loop approaches that integrate data analysis in the experimental design ease the investigation of sensory systems in three directions: First, adaptive sampling speeds up the data acquisition and thus increases the yield of an experiment. Second, model-driven stimulus exploration improves the quality of experimental data needed to discriminate between alternative hypotheses. Third, information-theoretic data analyses open up novel ways to search for those stimuli that are most efficient in driving a given neuron in terms of its firing rate or coding quality. Examples from different sensory systems show that, in all three directions, substantial progress can be achieved once rapid online data analysis, adaptive sampling, and computational modeling are tightly integrated into experiments. [Abstract]

Cull-Candy S, Klein R
Signalling mechanisms.
Curr Opin Neurobiol. 2007 Jun;17(3):277-80. [Abstract]

Torres GE, Amara SG
Glutamate and monoamine transporters: new visions of form and function.
Curr Opin Neurobiol. 2007 Jun;17(3):304-12.
Neurotransmitters are rapidly removed from the extracellular space primarily through the actions of plasma membrane transporters. This uptake process is not only essential in the termination of neurotransmission but also serves to replenish intracellular levels of transmitter for further release. Neurotransmitter transporters couple the inward movement of substrate to the movement of Na(+) down a concentration gradient and, in addition to their transport function, some carriers also display channel-like activities. Five Na(+)/K(+)-dependent glutamate transporter subtypes belong to the solute carrier 1 (SLC1) family and a second family, SLC6, encompasses the Na(+)/Cl(-)-dependent transporters for dopamine, 5-hydroxytryptamine (serotonin), noradrenaline, GABA and glycine. Recent advances, including high-resolution structures from both families, are now providing new insights into the molecular determinants that contribute to substrate translocation and ion channel activities. Other influential studies have explored how cellular regulatory mechanisms modulate transporter function, and how the different functions of the carrier shape the patterns of neurotransmitter signaling. This review focuses on recent studies of glutamate and monoamine transporters as prototypes of the two carrier families. [Abstract]

Dodson MW, Guo M
Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease.
Curr Opin Neurobiol. 2007 Jun;17(3):331-7.
Mutations in PARKIN, PTEN-induced kinase 1 (PINK1) and DJ-1 are found in autosomal recessive forms and some sporadic cases of Parkinson's disease. Recent work on these genes underscores the central importance of mitochondrial dysfunction and oxidative stress in Parkinson's disease. In particular, pink1 and parkin loss-of-function mutants in Drosophila show similar phenotypes, and pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial function. DJ-1 has a role in oxidative stress protection, but a direct role of DJ-1 in mitochondrial function has not been fully established. Importantly, defects in mitochondrial function have also been identified in patients who carry both PINK1 and PARKIN mutations, and in those who have sporadic Parkinson's disease. Future studies of the biochemical interactions between Pink1 and Parkin, and identification of other components in this pathway, are likely to provide insight into Parkinson's disease pathogenesis, and might identify new therapeutic targets. [Abstract]

Masugi-Tokita M, Shigemoto R
High-resolution quantitative visualization of glutamate and GABA receptors at central synapses.
Curr Opin Neurobiol. 2007 Jun;17(3):387-93.
Glutamate and GABA are the main transmitters in the central nervous system and their effects are mediated by ionotropic and metabotropic receptors. Immunogold electron microscopy has revealed the quantitative localization of these receptors at 20-30nm resolution. SDS-digested freeze-fracture replica labeling (SDS-FRL), a newly developed immunogold method, provides an accurate estimate of molecule numbers. Here, we summarize the recent advances in quantitative receptor localization, including use of SDS-FRL analyses to determine numbers of AMPA-type glutamate receptors in the cerebellum. The two-dimensional view and high sensitivity of SDS-FRL have revealed small, irregularly shaped AMPA receptor clusters within cerebellar synapses. [Abstract]

Mayford M
Protein kinase signaling in synaptic plasticity and memory.
Curr Opin Neurobiol. 2007 Jun;17(3):313-7.
The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity. [Abstract]

Recent Articles in Frontiers in Neuroendocrinology

de Kloet ER, Karst H, Jo�ls M
Corticosteroid hormones in the central stress response: Quick-and-slow.
Front Neuroendocrinol. 2007 Oct 24;
Recent evidence shows that corticosteroid hormones exert rapid non-genomic effects on neurons in the hypothalamus and the hippocampal CA1 region. The latter depend on classical mineralocorticoid receptors which are accessible from the outside of the plasma membrane and display a 10-fold lower affinity for corticosterone than the nuclear version involved in neuroprotection. Consequently, this 'membrane' receptor could play an important role while corticosteroid levels are high, i.e. during the initial phase of the stress response. We propose that during this phase corticosterone promotes hippocampal excitability and amplifies the effect of other stress hormones. These permissive non-genomic effects may contribute to fast behavioral effects and encoding of stress-related information. The fast effects are complemented by slower glucocorticoid receptor-mediated effects which facilitate suppression of temporary raised excitability, recovery from the stressful experience and storage of information for future use. [Abstract]

Hauser F, Cazzamali G, Williamson M, Park Y, Li B, Tanaka Y, Predel R, Neupert S, Schachtner J, Verleyen P, Grimmelikhuijzen CJ
A genome-wide inventory of neurohormone GPCRs in the red flour beetle Tribolium castaneum.
Front Neuroendocrinol. 2007 Oct 24;
Insect neurohormones (biogenic amines, neuropeptides, and protein hormones) and their G protein-coupled receptors (GPCRs) play a central role in the control of behavior, reproduction, development, feeding and many other physiological processes. The recent completion of several insect genome projects has enabled us to obtain a complete inventory of neurohormone GPCRs in these insects and, by a comparative genomics approach, to analyze the evolution of these proteins. The red flour beetle Tribolium castaneum is the latest addition to the list of insects with a sequenced genome and the first coleopteran (beetle) to be sequenced. Coleoptera is the largest insect order and about 30% of all animal species living on earth are coleopterans. Some coleopterans are severe agricultural pests, which is also true for T. castaneum, a global pest for stored grain and other dried commodities for human consumption. In addition, T. castaneum is a model for insect development. Here, we have investigated the presence of neurohormone GPCRs in Tribolium and compared them with those from the fruit fly Drosophila melanogaster (Diptera) and the honey bee Apis mellifera (Hymenoptera). We found 20 biogenic amine GPCRs in Tribolium (21 in Drosophila; 19 in the honey bee), 48 neuropeptide GPCRs (45 in Drosophila; 35 in the honey bee), and 4 protein hormone GPCRs (4 in Drosophila; 2 in the honey bee). Furthermore, we identified the likely ligands for 45 of these 72 Tribolium GPCRs. A highly interesting finding in Tribolium was the occurrence of a vasopressin GPCR and a vasopressin peptide. So far, the vasopressin/GPCR couple has not been detected in any other insect with a sequenced genome (D. melanogaster and six other Drosophila species, Anopheles gambiae, Aedes aegypti, Bombyx mori, and A. mellifera). Tribolium lives in very dry environments. Vasopressin in mammals is the major neurohormone steering water reabsorption in the kidneys. Its presence in Tribolium, therefore, might be related to the animal's need to effectively control water reabsorption. Other striking differences between Tribolium and the other two insects are the absence of the allatostatin-A, kinin, and corazonin neuropeptide/receptor couples and the duplications of other hormonal systems. Our survey of 340 million years of insect neurohormone GPCR evolution shows that neuropeptide/receptor couples can easily duplicate or disappear during insect evolution. It also shows that Drosophila is not a good representative of all insects, because several of the hormonal systems that we now find in Tribolium do not exist in Drosophila. [Abstract]

Haller J, Mikics E, Makara GB
The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings.
Front Neuroendocrinol. 2007 Oct 24;
Mounting evidence suggests that-beyond the well-known genomic effects-glucocorticoids affect cell function via non-genomic mechanisms. Such mechanisms operate in many major systems and organs including the cardiovascular, immune, endocrine and nervous systems, smooth and skeletal muscles, liver, and fat cells. Non-genomic effects are exerted by direct actions on membrane lipids (affecting membrane fluidity), membrane proteins (e.g. ion channels and neurotransmitter receptors), and cytoplasmic proteins (e.g. MAPKs, phospholipases, protein kinases, etc.). These actions are mediated by the glucocorticoids per se or by the proteins dissociated from the liganded glucocorticoid receptor complex. The MR and GR also activate non-genomic mechanisms in certain cases. Some effects of glucocorticoids are shared by a variety of steroids, whereas others are more selective. Moreover, "ultra-selective" effects-mediated by certain glucocorticoids only-were also shown. Disparate findings suggest that non-genomic mechanisms also show "demand-specificity", i.e. require the coincidence of two or more processes. Some of the non-genomic mechanisms activated by glucocorticoids are therapeutically relevant; moreover, the "non-genomic specificity" of certain glucocorticoids raises the possibility of therapeutic applications. Despite the large body of evidence, however, the non-genomic mechanisms of glucocorticoids are still poorly understood. Criteria for differentiating genomic and non-genomic mechanisms are often loosely applied; interactions between various mechanisms are unknown, and non-genomic mechanism-specific pharmacological (potentially therapeutic) agents are lacking. Nevertheless, the discovery of non-genomic mechanisms is a major breakthrough in stress research, and further insights into these mechanisms may open novel approaches for the therapy of various diseases. [Abstract]

Ghzili H, Grumolato L, Thou�nnon E, Tanguy Y, Turquier V, Vaudry H, Anouar Y
Role of PACAP in the physiology and pathology of the sympathoadrenal system.
Front Neuroendocrinol. 2007 Oct 22;
Sympathetic neurons and chromaffin cells derive from common sympathoadrenal precursors which arise from the neural crest. Cells from this lineage migrate to their final destination and differentiate by acquiring a catecholaminergic phenotype in response to different environmental factors. It has been shown that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its PAC1 receptor are expressed at early stages of sympathetic development, and participate to the control of neuroblast proliferation and differentiation. PACAP also acts as a neurotransmitter to stimulate catecholamine and neuropeptide biosynthesis and release from sympathetic neurons and chromaffin cells, during development and in adulthood. In addition, PACAP and its receptors have been described in neuroblastoma and pheochromocytoma, and the neuropeptide regulates the differentiation and activity of sympathoadrenal-derived tumoral cell lines, suggestive of an important role in the pathophysiology of the sympathoadrenal lineage. Transcriptome studies uncovered genes and pathways of known and unknown roles that underlie the effects of PACAP in the sympathoadrenal system. [Abstract]

Sladek CD, Somponpun SJ
Estrogen receptors: Their roles in regulation of vasopressin release for maintenance of fluid and electrolyte homeostasis.
Front Neuroendocrinol. 2007 Oct 12;
Long standing interest in the impact of gonadal steroid hormones on fluid and electrolyte balance has led to a body of literature filled with conflicting reports about gender differences, the effects of gonadectomy, hormone replacement, and reproductive cycles on plasma vasopressin (VP), VP secretion, and VP gene expression. This reflects the complexity of gonadal steroid hormone actions in the body resulting from multiple sites of action that impact fluid and electrolyte balance (e.g. VP target organs, afferent pathways regulating the VP neurons, and the VP secreting neurons themselves). It also reflects involvement of multiple types of estrogen receptors (ER) in these diverse sites including ERs that act as transcription factors regulating gene expression (i.e. the classic ERalpha as well as the more recently discovered ERbeta) and potentially G-protein coupled, membrane localized ERs that mediate rapid non-genomic actions of estrogen. Furthermore, altered expression of these receptors in physiologically diverse conditions of fluid and electrolyte balance contributes to the difficulty of using simplistic approaches such as gender comparisons, gonadectomy, and hormone replacement to assess the role of gonadal steroids in regulation of VP secretion for maintenance of fluid and electrolyte homeostasis. This review catalogs these inconsistencies and provides a frame work for understanding them by describing: (1) the effect of gonadal steroids on target organ responsiveness to VP; (2) the expression of multiple types of estrogen receptors in the VP neurons and in brain regions monitoring feedback signals from the periphery; and (3) the impact of dehydration and hyponatremia on expression of these receptors. [Abstract]

Michels G, Hoppe UC
Rapid actions of androgens.
Front Neuroendocrinol. 2007 Oct 5;
The biological activity of androgens is thought to occur predominantly through binding to intracellular androgen-receptors, a member of the nuclear receptor family, that interact with specific nucleotide sequences to alter gene expression. This genomic-androgen effect typically takes at least more than half an hour. In contrast, the rapid or non-genomic actions of androgens are manifested within in seconds to few minutes. This rapid effect of androgens are manifold, ranging from activation of G-protein coupled membrane androgen-receptors or sex hormone-binding globulin receptors, stimulation of different protein kinases, to direct modulation of voltage- and ligand gated ion-channels and transporters. The physiological relevance of these non-genomic androgen actions has not yet been determined in detail. However, it may contribute to modulate several second messenger systems or transcription factors, which suggests a cross-talk between the fast non-genomic and the slow genomic pathway of androgens. This review will focus on the rapid effects of androgens on cell surface and cytoplasmic level. [Abstract]

Davis PJ, Leonard JL, Davis FB
Mechanisms of nongenomic actions of thyroid hormone.
Front Neuroendocrinol. 2007 Oct 5;
The nongenomic actions of thyroid hormone require a plasma membrane receptor or nuclear receptors located in cytoplasm. The plasma membrane receptor is located on integrin alphaVbeta3 at the Arg-Gly-Asp recognition site important to the binding by the integrin of extracellular matrix proteins. l-Thyroxine (T(4)) is bound with greater affinity at this site than 3,5,3'-triiodo-l-thyronine (T(3)). Mitogen-activated protein kinase (MAPK; ERK1/2) transduces the hormone signal into complex cellular/nuclear events including angiogenesis and tumor cell proliferation. Acting at the integrin receptor and without cell entry, thyroid hormone can foster ERK1/2-dependent serine phosphorylation of nuclear thyroid hormone receptor-beta1 (TRbeta1) and de-repress the latter. The integrin receptor also mediates actions of the hormone on intracellular protein trafficking and on plasma membrane ion pumps, including the sodium/protein antiporter. Tetraiodothyroacetic (tetrac) is a T(4) analog that inhibits binding of iodothyronines to the integrin receptor and is a probe for the participation of this receptor in cellular actions of the hormone. Tetrac blocks thyroid hormone effects on angiogenesis and cancer cell proliferation. Acting on a truncated form of nuclear TRalpha1 (TRDeltaalpha1) located in cytoplasm, T(4) and 3,3',5'-triiodothyronine (reverse T(3)), but not T(3), cause conversion of soluble actin to fibrous (F) actin that is important to cell motility, e.g., in cells such as glia and neurons. Normal development of the central nervous system requires such motility. TRbeta1 in cytoplasm mediates action of T(3) on expression of certain genes via phosphatidylinositol 3-kinase (PI 3-K) and the protein kinase B/Akt pathway. PI 3-K and, possibly, cytoplasmic TRbeta1 are involved in stimulation by T(3) of insertion of Na,K-ATPase in the plasma membrane and of increase in activity of this pump. Because ambient thyroid hormone levels are constant in the euthyroid intact organism, these nongenomic hormone actions are likely to be contributors to basal rate-setting of transcription of certain genes and of complex cellular events such as angiogenesis and cancer cell proliferation. [Abstract]

Sherwin BB, Henry JF
Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: A critical review.
Front Neuroendocrinol. 2007 Oct 1;
Although there is now a substantial literature on the putative neuroprotective effects of estrogen on cognitive functioning in postmenopausal women, it is replete with inconsistencies. The critical period hypothesis, posited several years ago, attempts to account for the discrepancies in this literature by positing that estrogen treatment (ET) will protect aspects of cognition in older women only when treatment is initiated soon after the menopause. Indeed, evidence from basic neuroscience and from the animal and human literature reviewed herein provides compelling support for the critical period hypothesis. Although it is not known with certainty why estrogen does not protect cognition and may even cause harm when administered to women over the age of 65years, it is likely that the events that characterize brain aging, such as a reduction in brain volume and in neuronal size, alterations in neurotransmitter systems, and a decrease in dendritic spine numbers, form an unfavorable background that precludes a neuroprotective effects of exogenous estrogen on the brain. Other factors that have likely contributed to the discrepancies in the estrogen-cognition literature include differences in the estrogen compounds used, their route of administration, cyclic versus continuous regimens, and the concomitant use of progestins. This critical analysis attempts to define conditions under which ET may protect aspects of cognition in aging women while also considering the cost/benefit ratio for the treatment of women aged 50-59years. Suggestions for specific future research questions are also addressed. [Abstract]

L�sel RM, Wehling M
Classic versus non-classic receptors for nongenomic mineralocorticoid responses: Emerging evidence.
Front Neuroendocrinol. 2007 Oct 1;
Mineralocorticoids, which are synthesized locally in the central nervous system in addition to their adrenal production, trigger both genomic and nongenomic responses. Several functions of mineralocorticoids in the CNS are known to date, which are reviewed along with nongenomic responses in other tissues. A controversy regarding the identity of receptors that mediate nongenomic, transcription-independent cellular responses to steroids is presently attracting considerable scientific interest. While there is strong evidence for classic receptors belonging to the nuclear receptor superfamily to mediate nongenomic steroid effects in some cases, it does not exist for others. Recent findings on new and unexpected properties of classic receptors have partially withdrawn the interest from novel, non-classic membrane receptors, which are being progressively identified at present. This has been facilitated by the robust and elaborate toolkit for classic receptor studies in contrast to the comparably immature research tools for alternative receptors. To know the nature of receptors involved may be the key to beneficial medical translation of specific and targeted steroid responses. [Abstract]

Nyby JG
Reflexive testosterone release: A model system for studying the nongenomic effects of testosterone upon male behavior.
Front Neuroendocrinol. 2007 Oct 1;
Male mammals of many species exhibit reflexive testosterone release in mating situations. In house mice (Mus musculus), the dramatic robustness of such release, occurring primarily in response to a novel female, suggests some function. The resulting testosterone elevations typically peak during copulatory behavior and may serve to activate transitory motivational and physiological responses that facilitate reproduction. However, such a function requires that testosterone be working through either nongenomic, or very quick genomic, mechanisms. The first part of the review describes reflexive sex hormone release in house mice. The second part summarizes research implicating testosterone's fast actions in affecting anxiety, reward, learning, analgesia, and penile reflexes in rodents, all of which could optimize male mating success. The review concludes with a speculative model of how spontaneous and reflexive hormone release might interact to regulate reproductive behavior and why mice appear to be an ideal species for examining testosterone's quick effects. [Abstract]

Millar RP, Pawson AJ, Morgan K, Rissman EF, Lu ZL
Diversity of actions of GnRHs mediated by ligand-induced selective signaling.
Front Neuroendocrinol. 2007 Aug 23;
Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G(q) signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention. [Abstract]

Ohno K, Sakurai T
Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness.
Front Neuroendocrinol. 2007 Aug 29;
Orexin A and orexin B were initially identified as endogenous ligands for two orphan G protein-coupled receptors [104]. They were initially recognized as regulators of feeding behavior in view of their exclusive production in the lateral hypothalamic area (LHA), a region known as the feeding center, and their pharmacological activity [104,30,49,107]. Subsequently, the finding that orexin deficiency causes narcolepsy in humans and animals suggested that these hypothalamic neuropeptides play a critical role in regulating sleep/wake cycle [22,46,71,95,117]. These peptides activate waking-active monoaminergic and cholinergic neurons in the hypothalamus/brain stem regions to maintain a long, consolidated awake period. Recent studies on efferent and afferent systems of orexin neurons, and phenotypic characterization of genetically modified mice in the orexin system further suggested roles of orexin in the coordination of emotion, energy homeostasis, reward system, and arousal [3,80,106,137]. A link between the limbic system and orexin neurons might be important for increasing vigilance during emotional stimuli. Orexin neurons are also regulated by peripheral metabolic cues, including ghrelin, leptin, and glucose, suggesting that they might have important roles as a link between energy homeostasis and vigilance states [137]. Recent research has also implicated orexins in reward systems and the mechanisms of drug addiction [13,48,91]. These observations suggest that orexin neurons sense the outer and inner environment of the body, and maintain proper wakefulness of animals for survival. This review discusses the mechanism by which orexins maintain sleep/wakefulness states, and how this mechanism relates to other systems that regulate emotion, reward, and energy homeostasis. [Abstract]

Becker JB, Hu M
Sex differences in drug abuse.
Front Neuroendocrinol. 2007 Aug 24;
Sex differences are present for all of the phases of drug abuse (initiation, escalation of use, addiction, and relapse following abstinence). While there are some differences among specific classes of abused drugs, the general pattern of sex differences is the same for all drugs of abuse. Females begin regularly self-administering licit and illicit drugs of abuse at lower doses than do males, use escalates more rapidly to addiction, and females are at greater risk for relapse following abstinence. In this review, sex differences in drug abuse are discussed for humans and in animal models. The possible neuroendocrine mechanisms mediating these sex differences are discussed. [Abstract]

Roa J, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M
New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function.
Front Neuroendocrinol. 2007 Aug 11;
Identification, in late 2003, of inactivating mutations of the G protein-coupled receptor GPR54 as causative factor for absence of puberty and hypogonadotropic hypogonadism in humans and mice was a major breakthrough in modern Neuroendocrinology, and drew considerable interest on the characterization of the roles of this receptor and its ligands (kisspeptins, encoded by the KiSS-1 gene) in the physiological control of essential facets of reproduction. After 3 years of intense research activity, kisspeptins are universally recognized as essential activators of the gonadotropic axis, with key roles in puberty onset and the control of gonadotropin secretion. While these fundamental functions are now well settled, novel aspects of kisspeptin/GPR54 physiology have emerged, including their involvement in the neuroendocrine control of ovulation and the metabolic gating of reproductive function. In addition, the 'comparative endocrinology' of this system has begun to be explored recently. These facets of kisspeptin/GPR54 function, as fundamental gatekeepers of reproduction, will be comprehensively reviewed herein. [Abstract]

Panzica GC, Viglietti-Panzica C, Mura E, Quinn MJ, Lavoie E, Palanza P, Ottinger MA
Effects of xenoestrogens on the differentiation of behaviorally-relevant neural circuits.
Front Neuroendocrinol. 2007 Oct;28(4):179-200.
It has become increasingly clear that environmental chemicals have the capability of impacting endocrine function. Moreover, these endocrine disrupting chemicals (EDCs) have long term consequences on adult reproductive function, especially if exposure occurs during embryonic development thereby affecting sexual differentiation. Of the EDCs, most of the research has been conducted on the effects of estrogen active compounds. Although androgen active compounds are also present in the environment, much less information is available about their action. However, in the case of xenoestrogens, there is mounting evidence for long-term consequences of early exposure at a range of doses. In this review, we present data relative to two widely used animal models: the mouse and the Japanese quail. These two species long have been used to understand neural, neuroendocrine, and behavioral components of reproduction and are therefore optimal models to understand how these components are altered by precocious exposure to EDCs. In particular we discuss effects of bisphenol A and methoxychlor on the dopaminergic and noradrenergic systems in rodents and the impact of these alterations. In addition, the effects of embryonic exposure to diethylstilbestrol, genistein or ethylene,1,1-dichloro-2,2-bis(p-chlorophenyl) is reviewed relative to behavioral impairment and associated alterations in the sexually dimorphic parvocellular vasotocin system in quail. We point out how sexually dimorphic behaviors are particularly useful to verify adverse developmental consequences produced by chemicals with endocrine disrupting properties, by examining either reproductive or non-reproductive behaviors. [Abstract]

Bakker J, Baum MJ
Role for estradiol in female-typical brain and behavioral sexual differentiation.
Front Neuroendocrinol. 2007 Jul 26;
The importance of estrogens in controlling brain and behavioral sexual differentiation in female rodents is an unresolved issue in the field of behavioral neuroendocrinology. Whereas, the current dogma states that the female brain develops independently of estradiol, many studies have hinted at possible roles of estrogen in female sexual differentiation. Accordingly, it has been proposed that alpha-fetoprotein, a fetal plasma protein that binds estrogens with high affinity, has more than a neuroprotective role and specifically delivers estrogens to target brain cells to ensure female differentiation. Here, we review new results obtained in aromatase and alpha-fetoprotein knockout mice showing that estrogens can have both feminizing and defeminizing effects on the developing neural mechanisms that control sexual behavior. We propose that the defeminizing action of estradiol normally occurs prenatally in males and is avoided in fetal females because of the protective actions of alpha-fetoprotein, whereas the feminizing action of estradiol normally occurs postnatally in genetic females. [Abstract]

Takei Y, Ogoshi M, Inoue K
A 'reverse' phylogenetic approach for identification of novel osmoregulatory and cardiovascular hormones in vertebrates.
Front Neuroendocrinol. 2007 Oct;28(4):143-60.
Vertebrates expanded their habitats from aquatic to terrestrial environments during the course of evolution. In parallel, osmoregulatory and cardiovascular systems evolved to counter the problems of desiccation and gravity on land. In our physiological studies on body fluid and blood pressure regulation in various vertebrate species, we found that osmoregulatory and cardiovascular hormones have changed their structure and function during the transition from aquatic to terrestrial life. In fact, Na(+)-regulating and vasodepressor hormones play essential roles in fishes, while water-regulating and vasopressor hormones are dominant in tetrapods. Accordingly, Na(+)-regulating and vasodepressor hormones, such as natriuretic peptide (NP) and adrenomedullin (AM), are much diversified in teleost fishes compared with mammals. Based on this finding, new NPs and AMs were identified in mammals and other tetrapods. These hormones have only minor roles in the maintenance of normal blood volume and pressure in mammals, but their importance seems to increase when homeostasis is disrupted. Therefore, such hormones can be used for diagnosis and treatment of body fluid and cardiovascular disorders such as cardiac/renal failure and hypertension. In this review, we introduce a new approach for identification of novel Na(+)-regulating and vasodepressor hormones in mammals based on fish studies. Until recently, new hormones were first discovered in mammals, and then identified and applied in fishes. However, chances are increasing in recent years to identify new hormones first in fishes then in mammals, based on the difference in the regulatory systems between fishes and tetrapods. As the direction is opposite from the traditional phylogenetic approach, we added 'reverse' to its name. The 'reverse' phylogenetic approach offers a typical example of how comparative fish studies can contribute to the general and clinical endocrinology. [Abstract]

Balthazart J, Ball GF
Topography in the preoptic region: differential regulation of appetitive and consummatory male sexual behaviors.
Front Neuroendocrinol. 2007 Oct;28(4):161-78.
Several studies have suggested dissociations between neural circuits underlying the expression of appetitive (e.g., courtship behavior) and consummatory components (i.e., copulatory behavior) of vertebrate male sexual behavior. The medial preoptic area (mPOA) clearly controls the expression of male copulation but, according to a number of experiments, is not necessarily implicated in the expression of appetitive sexual behavior. In rats for example, lesions to the mPOA eliminate male-typical copulatory behavior but have more subtle or no obvious effects on measures of sexual motivation. Rats with such lesions still pursue and attempt to mount females. They also acquire and perform learned instrumental responses to gain access to females. However, recent lesions studies and measures of the expression of the immediate early gene c-fos demonstrate that, in quail, sub-regions of the mPOA, in particular of its sexually dimorphic component the medial preoptic nucleus, can be specifically linked with either the expression of appetitive or consummatory sexual behavior. In particular more rostral regions can be linked to appetitive components while more caudal regions are involved in consummatory behavior. This functional sub-region variation is associated with neurochemical and hodological specializations (i.e., differences in chemical phenotype of the cells or in their connectivity), especially those related to the actions of androgens in relation to the activation of male sexual behavior, that are also present in rodents and other species. It could thus reflect general principles about POA organization and function in the vertebrate brain. [Abstract]

Lonstein JS
Regulation of anxiety during the postpartum period.
Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):115-41.
Healthy mother-infant interactions are critical for the physical, cognitive, and psychological development of offspring. Such interactions rely on numerous factors, including a positive maternal emotional state. However, many postpartum women experience emotional dysregulation, often involving elevated anxiety. Neuroendocrine factors contributing to the onset of postpartum anxiety symptoms are mostly unknown, but irregularities in hypothalamic-pituitary-adrenal axis function, reduced prolactin and oxytocin signaling, or parturitional withdrawal of ovarian, placental and neural steroids could contribute to anxiety in susceptible women. Although the causes of initial onset are unclear, postpartum anxiety can be mitigated by recent contact with infants. Numerous neurochemical systems, including oxytocin, prolactin, GABA, and norepinephrine mediate this anxiolytic effect of infant contact. Insight into the etiology of postpartum anxiety disorders, and how contact with infants helps counter existing anxiety dysregulation, will surely facilitate the diagnosis and treatment of postpartum women at risk for, or experiencing, an anxiety disorder. [Abstract]

Fekete C, Lechan RM
Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons: role of neuronal afferents and type 2 deiodinase.
Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):97-114.
Hypophysiotropic thyrotropin-releasing hormone (TRH): synthesizing neurons reside in the hypothalamic paraventricular nucleus (PVN) and are the central regulators of the hypothalamic-pituitary-thyroid (HPT) axis. TRH synthesis and release from these neurons are primarily under negative feedback regulation by thyroid hormone. Under certain conditions such as cold exposure and fasting, however, inputs from neurons in the brainstem and hypothalamic arcuate and dorsomedial nuclei alter the set point for negative feedback through regulation of CREB phosphorylation. Thus, during cold exposure, adrenergic neurons stimulate the HPT axis, while fasting-induced central hypothyroidism is mediated through an arcuato-paraventricular pathway. Feedback regulation of TRH neurons may also be modified by local tissue levels of thyroid hormone regulated by the activation of type 2 iodothyronine deiodinase (D2), the primary enzyme in the brain that catalyzes T4 to T3 conversion. During infection, endotoxin or endotoxin induced cytokines increase D2 activity in the mediobasal hypothalamus, which by inducing local hyperthyroidism, may play an important role in infection-induced inhibition of hypophysiotropic TRH neurons. [Abstract]

Jo�ls M, Karst H, Krugers HJ, Lucassen PJ
Chronic stress: implications for neuronal morphology, function and neurogenesis.
Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):72-96.
In normal life, organisms are repeatedly exposed to brief periods of stress, most of which can be controlled and adequately dealt with. The presently available data indicate that such brief periods of stress have little influence on the shape of neurons or adult neurogenesis, yet change the physiological function of cells in two time-domains. Shortly after stress excitability in limbic areas is rapidly enhanced, but also in brainstem neurons which produce catecholamines; collectively, during this phase the stress hormones promote focused attention, alertness, vigilance and the initial steps in encoding of information linked to the event. Later on, when the hormone concentrations are back to their pre-stress level, gene-mediated actions by corticosteroids reverse and normalize the enhanced excitability, an adaptive response meant to curtail defense reactions against stressors and to enable further storage of relevant information. When stress is experienced repetitively in an uncontrollable and unpredictable manner, a cascade of processes in brain is started which eventually leads to profound, region-specific alterations in dendrite and spine morphology, to suppression of adult neurogenesis and to inappropriate functional responses to a brief stress exposure including a sensitized activation phase and inadequate normalization of brain activity. Although various compounds can effectively prevent these cellular changes by chronic stress, the exact mechanism by which the effects are accomplished is poorly understood. One of the challenges for future research is to link the cellular changes seen in animal models for chronic stress to behavioral effects and to understand the risks they can impose on humans for the precipitation of stress-related disorders. [Abstract]

Froy O
The relationship between nutrition and circadian rhythms in mammals.
Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):61-71.
The master clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus regulates circadian rhythms in mammals. The clock is an intracellular, transcriptional mechanism sharing the same molecular components in SCN neurons and in peripheral cells, such as the liver, intestine, and retina. The circadian clock controls food processing and energy homeostasis by regulating the expression and/or activity of enzymes involved in cholesterol, amino acid, lipid, glycogen, and glucose metabolism. In addition, many hormones involved in metabolism, such as insulin, glucagon, adiponectin, corticosterone, leptin, and ghrelin, exhibit circadian oscillation. Furthermore, disruption of circadian rhythms is involved in the development of cancer, metabolic syndrome, and obesity. Metabolism and food intake also feed back to influence the biological clock. Calorie restriction (CR) entrains the SCN clock, whereas timed meals entrain peripheral oscillators. Furthermore, the cellular redox state, dictated by food metabolism, and several nutrients, such as glucose, ethanol, adenosine, caffeine, thiamine, and retinoic acid, can phase-shift circadian rhythms. In conclusion, there is a large body of evidence that links feeding regimens, food components, and the biological clock. [Abstract]

Rinaman L
Visceral sensory inputs to the endocrine hypothalamus.
Front Neuroendocrinol. 2007 Apr;28(1):50-60.
Interoceptive feedback signals from the body are transmitted to hypothalamic neurons that control pituitary hormone release. This review article describes the organization of central neural pathways that convey ascending visceral sensory signals to endocrine neurons in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in rats. A special emphasis is placed on viscerosensory inputs to corticotropin releasing factor (CRF)-containing PVN neurons that drive the hypothalamic-pituitary-adrenal axis, and on inputs to magnocellular PVN and SON neurons that release vasopressin (AVP) or oxytocin (OT) from the posterior pituitary. The postnatal development of these ascending pathways also is considered. [Abstract]

Bartolomucci A
Social stress, immune functions and disease in rodents.
Front Neuroendocrinol. 2007 Apr;28(1):28-49.
The link between social factors, stress and health has been the focus of many interdisciplinary studies mostly because: (i) animals, including humans, often live in societies; (ii) positive and negative social relationships affect disease and well being; (iii) physiological alterations, which parallel social interactions also modulate immune and neuroendocrine functions. This review will focus on studies conducted on laboratory and wild rodents where social factors such as dyadic interactions, individual housing and differential group housing were investigated. The results obtained allow one to conclude that social factors in rodents are causally linked with immune disorders/disease susceptibility. In particular, lower lymphocyte proliferation and antigen-specific-IgG, granulocytosis and lymphopenia, as well as higher tumor induction and progression, are reliably associated with negative social events. Finally, due to the increasing utilization of social stress-based animal models the reliability of the concept of "social stress" and its evolutionary context are re-evaluated. [Abstract]

Fekete EM, Zorrilla EP
Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs.
Front Neuroendocrinol. 2007 Apr;28(1):1-27.
Urocortins, three paralogs of the stress-related peptide corticotropin-releasing factor (CRF) found in bony fish, amphibians, birds, and mammals, have unique phylogenies, pharmacologies, and tissue distributions. As a result and despite a structural family resemblance, the natural functions of urocortins and CRF in mammalian homeostatic responses differ substantially. Endogenous urocortins are neither simply counterpoints nor mimics of endogenous CRF action. In their own right, urocortins may be clinically relevant molecules in the pathogenesis or management of many conditions, including congestive heart failure, hypertension, gastrointestinal and inflammatory disorders (irritable bowel syndrome, active gastritis, gastroparesis, and rheumatoid arthritis), atopic/allergic disorders (dermatitis, urticaria, and asthma), pregnancy and parturition (preeclampsia, spontaneous abortion, onset, and maintenance of effective labor), major depression and obesity. Safety trials for intravenous urocortin treatment have already begun for the treatment of congestive heart failure. Further understanding the unique functions of urocortin 1, urocortin 2, and urocortin 3 action may uncover other therapeutic opportunities. [Abstract]

Sohrabji F, Lewis DK
Estrogen-BDNF interactions: implications for neurodegenerative diseases.
Front Neuroendocrinol. 2006 Dec;27(4):404-14.
Since its' discovery over 20 years ago, BDNF has been shown to play a key role in neuronal survival, in promoting neuronal regeneration following injury, regulating transmitter systems and attenuating neural-immune responses. Estrogen's actions in the young and mature brain, and its role in neurodegenerative diseases in many cases overlaps with those observed for BDNF. Reduced estrogen and BDNF are observed in patients with Parkinson's disease and Alzheimer's disease, while high estrogen levels are a risk factor for development of multiple sclerosis. Estrogen receptors, which transduce the actions of estrogen, colocalize to cells that express BDNF and its receptor trkB, and estrogen further regulates the expression of this neurotrophin system. This review describes the distribution of BDNF and trkB expressing cells in the forebrain, and the roles of estrogen and the BDNF-trkB neurotrophin system in Parkinson's disease, Alzheimer's disease and multiple sclerosis. [Abstract]

Scharfman HE, MacLusky NJ
Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS.
Front Neuroendocrinol. 2006 Dec;27(4):415-35.
In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, and predicted that the effects of estrogen, at least in part, might be due to the induction of BDNF. This hypothesis is discussed with respect to the hippocampus, where substantial evidence has accumulated in favor of it, but alternate hypotheses are also raised. It is suggested that some of the interactions between estrogen and BDNF, as well as the controversies and implications associated with their respective actions, may be best appreciated in light of the ability of BDNF to induce neuropeptide Y (NPY) synthesis in hippocampal neurons. Taken together, this tri-molecular cascade, estrogen-BDNF-NPY, may be important in understanding the hormonal regulation of hippocampal function. It may also be relevant to other regions of the CNS where estrogen is known to exert profound effects, such as amygdala and hypothalamus; and may provide greater insight into neurological disorders and psychiatric illness, including Alzheimer's disease, depression and epilepsy. [Abstract]

Mendez P, Wandosell F, Garcia-Segura LM
Cross-talk between estrogen receptors and insulin-like growth factor-I receptor in the brain: cellular and molecular mechanisms.
Front Neuroendocrinol. 2006 Dec;27(4):391-403.
Accumulating evidence suggests that insulin-like growth factor-I (IGF-I) and estradiol interact to regulate neural function. In this review, we focus on the cellular and molecular mechanisms involved in this interaction. The expression of estrogen receptors (ERs) and IGF-I receptor is cross-regulated in the central nervous system and many neurons and astrocytes coexpress both receptors. Furthermore, estradiol activates IGF-I receptor and its intracellular signaling. This effect may involve classical ERs since recent findings suggest that ERalpha may affect IGF-I actions in the brain by a direct interaction with some of the components of IGF-I signaling. In turn, IGF-I may regulate ER transcriptional activity in neuronal cells. In conclusion, ERs appear to be part of the signaling mechanism of IGF-I, and IGF-I receptor part of the mechanism of estradiol signaling in the nervous system. [Abstract]

Wagner CK
The many faces of progesterone: a role in adult and developing male brain.
Front Neuroendocrinol. 2006 Sep;27(3):340-59.
In addition to its well documented action in female-typical behaviors, progesterone exerts an influence on the brain and behavior of males. This review will discuss the role of progesterone and its receptor in male-typical reproductive behaviors in adulthood and the role of progesterone and its receptor in neural development, in both sexual differentiation of the brain as well as in the development of "non-reproductive" functions. The seemingly inconsistent and contradictory results on progesterone in males that exist in the literature illustrate the complexity of progesterone's actions and illuminate the need for further research in this area. As progestin-containing contraceptives in men are currently being tested and progesterone administration to pregnant women and premature newborns increases, a better understanding of the role of this hormone in behavior and brain development becomes essential. [Abstract]

Eva C, Serra M, Mele P, Panzica G, Oberto A
Physiology and gene regulation of the brain NPY Y1 receptor.
Front Neuroendocrinol. 2006 Sep;27(3):308-39.
Neuropeptide Y (NPY) is one of the most prominent and abundant neuropeptides in the mammalian brain where it interacts with a family of G-protein coupled receptors, including the Y(1) receptor subtype (Y(1)R). NPY-Y(1)R signalling plays a prominent role in the regulation of several behavioural and physiological functions including feeding behaviour and energy balance, sexual hormone secretion, stress response, emotional behaviour, neuronal excitability and ethanol drinking. Y(1)R expression is regulated by neuronal activity and peripheral hormones. The Y(1)R gene has been isolated from rodents and humans and it contains multiple regulatory elements that may participate in the regulation of its expression. Y(1)R expression in the hypothalamus is modulated by changes in energetic balance induced by a wide variety of conditions (fasting, pregnancy, hyperglycaemic challenge, hypophagia, diet induced obesity). Estrogens up-regulate responsiveness to NPY to stimulate preovulatory GnRH and gonadotropin surges by increasing Y(1)R gene expression both in the hypothalamus and the pituitary. Y(1)R expression is modulated by different kinds of brain insults, such as stress and seizure activity, and alteration in its expression may contribute to antidepressant action. Chronic modulation of GABA(A) receptor function by benzodiazepines or neuroactive steroids also affects Y(1)R expression in the amygdala, suggesting that a functional interaction between the GABA(A) receptor and Y(1)R mediated signalling may contribute to the regulation of emotional behaviour. In this paper, we review the state of the art concerning Y(1)R function and gene expression, including our personal contribution to many of the subjects mentioned above. [Abstract]

Recent Articles in The Journal of Neuroscience

Jo YS, Park EH, Kim IH, Park SK, Kim H, Kim HT, Choi JS
The medial prefrontal cortex is involved in spatial memory retrieval under partial-cue conditions.
J Neurosci. 2007 Dec 5;27(49):13567-78.
Brain circuits involved in pattern completion, or retrieval of memory from fragmented cues, were investigated. Using different versions of the Morris water maze, we explored the roles of the CA3 subregion of the hippocampus and the medial prefrontal cortex (mPFC) in spatial memory retrieval under various conditions. In a hidden platform task, both CA3 and mPFC lesions disrupted memory retrieval under partial-cue, but not under full-cue, conditions. For a delayed matching-to-place task, CA3 lesions produced a deficit in both forming and recalling spatial working memory regardless of extramaze cue conditions. In contrast, damage to mPFC impaired memory retrieval only when a fraction of cues was available. To corroborate the lesion study, we examined the expression of the immediate early gene c-fos in mPFC and the hippocampus. After training of spatial reference memory in full-cue conditions for 6 d, the same training procedure in the absence of all cues except one increased the number of Fos-immunoreactive cells in mPFC and CA3. Furthermore, mPFC inactivation with muscimol, a GABA agonist, blocked memory retrieval in the degraded-cue environment. However, mPFC-lesioned animals initially trained in a single-cue environment had no difficulty in retrieving spatial memory when the number of cues was increased, demonstrating that contextual change per se did not impair the behavioral performance of the mPFC-lesioned animals. Together, these findings strongly suggest that pattern completion requires interactions between mPFC and the hippocampus, in which mPFC plays significant roles in retrieving spatial information maintained in the hippocampus for efficient navigation. [Abstract]

Mercer JN, Chan CS, Tkatch T, Held J, Surmeier DJ
Nav1.6 sodium channels are critical to pacemaking and fast spiking in globus pallidus neurons.
J Neurosci. 2007 Dec 5;27(49):13552-66.
Neurons in the external segment of the globus pallidus (GPe) are autonomous pacemakers that are capable of sustained fast spiking. The cellular and molecular determinants of pacemaking and fast spiking in GPe neurons are not fully understood, but voltage-dependent Na+ channels must play an important role. Electrophysiological studies of these neurons revealed that macroscopic activation and inactivation kinetics of their Na+ channels were similar to those found in neurons lacking either autonomous activity or the capacity for fast spiking. What was distinctive about GPe Na+ channels was a prominent resurgent gating mode. This mode was significantly reduced in GPe neurons lacking functional Nav1.6 channels. In these Nav1.6 null neurons, pacemaking and the capacity for fast spiking were impaired, as was the ability to follow stimulation frequencies used to treat Parkinson's disease (PD). Simulations incorporating Na+ channel models with and without prominent resurgent gating suggested that resurgence was critical to fast spiking but not to pacemaking, which appeared to be dependent on the positioning of Na+ channels in spike-initiating regions of the cell. These studies not only shed new light on the mechanisms underlying spiking in GPe neurons but also suggest that electrical stimulation therapies in PD are unlikely to functionally inactivate neurons possessing Nav1.6 Na+ channels with prominent resurgent gating. [Abstract]

Lim HH, Lenarz T, Joseph G, Battmer RD, Samii A, Samii M, Patrick JF, Lenarz M
Electrical stimulation of the midbrain for hearing restoration: insight into the functional organization of the human central auditory system.
J Neurosci. 2007 Dec 5;27(49):13541-51.
The cochlear implant can restore speech perception in patients with sensorineural hearing loss. However, it is ineffective for those without an implantable cochlea or a functional auditory nerve. These patients can be implanted with the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus. Unfortunately, the ABI has achieved limited success in its main patient group [i.e., those with neurofibromatosis type 2 (NF2)] and requires a difficult surgical procedure. These limitations have motivated us to develop a new hearing prosthesis that stimulates the midbrain with a penetrating electrode array. We recently implanted three patients with the auditory midbrain implant (AMI), and it has proven to be safe with minimal movement over time. The AMI provides loudness, pitch, temporal, and directional cues, features that have shown to be important for speech perception and more complex sound processing. Thus far, all three patients obtain enhancements in lip reading capabilities and environmental awareness and some improvements in speech perception comparable with that of NF2 ABI patients. Considering that our midbrain target is more surgically exposable than the cochlear nucleus, this argues for the use of the AMI as an alternative to the ABI. Fortunately, we were able to stimulate different midbrain regions in our patients and investigate the functional organization of the human central auditory system. These findings provide some insight into how we may need to stimulate the midbrain to improve hearing performance with the AMI. [Abstract]

Grabenhorst F, Rolls ET, Margot C, da Silva MA, Velazco MI
How pleasant and unpleasant stimuli combine in different brain regions: odor mixtures.
J Neurosci. 2007 Dec 5;27(49):13532-40.
Many affective stimuli are hedonically complex mixtures containing both pleasant and unpleasant components. To investigate whether the brain represents the overall affective value of such complex stimuli, or the affective value of the different components simultaneously, we used functional magnetic resonance imaging to measure brain activations to a pleasant odor (jasmine), an unpleasant odor (indole), and a mixture of the two that was pleasant. In brain regions that represented the pleasantness of the odors such as the medial orbitofrontal cortex (as shown by activations that correlated with the pleasantness ratings), the mixture produced activations of similar magnitude to the pleasant jasmine, but very different from the unpleasant indole. These regions thus emphasize the pleasant aspects of the mixture. In contrast, in regions representing the unpleasantness of odors such as the dorsal anterior cingulate and midorbitofrontal cortex the mixture produced activations that were relatively further from the pleasant component jasmine and closer to the indole. These regions thus emphasize the unpleasant aspects of the mixture. Thus mixtures that are found pleasant can have components that are separately pleasant and unpleasant, and the brain can separately and simultaneously represent the positive and negative hedonic value of a complex affective stimulus that contains both pleasant and unpleasant olfactory components. This type of representation may be important for affective decision making in the brain in that separate representations of different affective components of the same sensory stimulus may provide the inputs for making a decision about whether to choose the stimulus or not. [Abstract]

Baldelli P, Fassio A, Valtorta F, Benfenati F
Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses.
J Neurosci. 2007 Dec 5;27(49):13520-31.
Synapsins (Syns) are synaptic vesicle (SV) phosphoproteins that play a role in neurotransmitter release and synaptic plasticity by acting at multiple steps of exocytosis. Mutation of SYN genes results in an epileptic phenotype in mouse and man suggesting a role of Syns in the control of network excitability. We have studied the effects of the genetic ablation of the SYN1 gene on inhibitory synaptic transmission in primary hippocampal neurons. Inhibitory neurons lacking SynI showed reduced amplitude of IPSCs evoked by isolated action potentials. The impairment in inhibitory transmission was caused by a decrease in the size of the SV readily releasable pool, rather than by changes in release probability or quantal size. The reduction of the readily releasable pool was caused by a decrease in the number of SVs released by single synaptic boutons in response to the action potential, in the absence of variations in the number of synaptic contacts between couples of monosynaptically connected neurons. The deletion of SYN1 did not affect paired-pulse depression or post-tetanic potentiation, but was associated with a moderate increase of synaptic depression evoked by trains of action potentials, which became apparent at high stimulation frequencies and was accompanied by a slow down of recovery from depression. The decreased size of the SV readily releasable pool, coupled with a decreased SV recycling rate and refilling by the SV reserve pool, may contribute to the epileptic phenotype of SynI knock-out mice. [Abstract]

Trevelyan AJ, Baldeweg T, van Drongelen W, Yuste R, Whittington M
The source of afterdischarge activity in neocortical tonic-clonic epilepsy.
J Neurosci. 2007 Dec 5;27(49):13513-9.
Tonic-clonic seizures represent a common pattern of epileptic discharges, yet the relationship between the various phases of the seizure remains obscure. Here we contrast propagation of the ictal wavefront with the propagation of individual discharges in the clonic phase of the event. In an in vitro model of tonic-clonic epilepsy, the afterdischarges (clonic phase) propagate with relative uniform speed and are independent of the speed of the ictal wavefront (tonic phase). For slowly propagating ictal wavefronts, the source of the afterdischarges, relative to a given recording electrode, switched as the wavefront passed by, indicating that afterdischarges are seeded from wavefront itself. In tissue that has experienced repeated ictal events, the wavefront generalizes rapidly, and the afterdischarges in this case show a different "flip-flop" pattern, with frequent switches in their direction of propagation. This same flip-flop pattern is also seen in subdural EEG recordings in patients suffering intractable focal seizures caused by cortical dysplasias. Thus, in both slowly and rapidly generalizing ictal events, there is not a single source of afterdischarge activity: rather, the source is continuously changing. Our data suggest a complex view of seizures in which the ictal event and its constituent discharges originate from distinct locations. [Abstract]

Han VZ, Zhang Y, Bell CC, Hansel C
Synaptic plasticity and calcium signaling in Purkinje cells of the central cerebellar lobes of mormyrid fish.
J Neurosci. 2007 Dec 5;27(49):13499-512.
Climbing fiber (CF)-evoked calcium transients play a key role in plasticity at parallel fiber (PF) to Purkinje cell synapses in the mammalian cerebellum. Whereas PF activation alone causes long-term potentiation (LTP), coactivation of the heterosynaptic CF input, which evokes large dendritic calcium transients, induces long-term depression (LTD). This unique type of heterosynaptic interaction is a hallmark feature of synaptic plasticity in mammalian Purkinje cells. Purkinje cells in the cerebellum of mormyrid electric fish are characterized by a different architecture of their dendritic trees and by a more pronounced separation of CF and PF synaptic contact sites. We therefore examined the conditions for bidirectional plasticity at PF synapses onto Purkinje cells in the mormyrid cerebellum in vitro. PF stimulation at elevated frequencies induces LTP, whereas LTD results from PF stimulation at enhanced intensities and depends on dendritic calcium influx and metabotropic glutamate receptor type 1 activation. LTD can also be observed after pairing of low intensity PF stimulation with CF stimulation. Using a combination of whole-cell patch-clamp recordings and fluorometric calcium imaging, we characterized calcium transients in Purkinje cell dendrites. CF activation elicits calcium transients not only within the CF input territory (smooth proximal dendrites) but also within the PF input territory (spiny palisade dendrites). Paired PF and CF activation elicits larger calcium transients than stimulation of either input alone. A major source for dendritic calcium signaling is provided by P/Q-type calcium channels. Our data show that despite the spatial separation between the two inputs CF activity facilitates LTD induction at PF synapses. [Abstract]

Jacobsen LK, Picciotto MR, Heath CJ, Frost SJ, Tsou KA, Dwan RA, Jackowski MP, Constable RT, Mencl WE
Prenatal and adolescent exposure to tobacco smoke modulates the development of white matter microstructure.
J Neurosci. 2007 Dec 5;27(49):13491-8.
Prenatal exposure to maternal smoking has been linked to cognitive and auditory processing deficits in offspring. Preclinical studies have demonstrated that exposure to nicotine disrupts neurodevelopment during gestation and adolescence, possibly by disrupting the trophic effects of acetylcholine. Given recent clinical and preclinical work suggesting that neurocircuits that support auditory processing may be particularly vulnerable to developmental disruption by nicotine, we examined white matter microstructure in 67 adolescent smokers and nonsmokers with and without prenatal exposure to maternal smoking. The groups did not differ in age, educational attainment, IQ, years of parent education, or symptoms of inattention. Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired, and auditory attention was assessed, in all subjects. Both prenatal exposure and adolescent exposure to tobacco smoke was associated with increased fractional anisotropy (FA) in anterior cortical white matter. Adolescent smoking was also associated with increased FA of regions of the internal capsule that contain auditory thalamocortical and corticofugal fibers. FA of the posterior limb of the left internal capsule was positively correlated with reaction time during performance of an auditory attention task in smokers but not in nonsmokers. Development of anterior cortical and internal capsule fibers may be particularly vulnerable to disruption in cholinergic signaling induced by nicotine in tobacco smoke. Nicotine-induced disruption of the development of auditory corticofugal fibers may interfere with the ability of these fibers to modulate ascending auditory signals, leading to greater noise and reduced efficiency of neurocircuitry that supports auditory processing. [Abstract]

Chumley MJ, Catchpole T, Silvany RE, Kernie SG, Henkemeyer M
EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis.
J Neurosci. 2007 Dec 5;27(49):13481-90.
The adult brain maintains two regions of neurogenesis from which new neurons are born, migrate to their appropriate location, and become incorporated into the circuitry of the CNS. One of these, the subgranular zone of the hippocampal dentate gyrus, is of primary interest because of the role of this region in learning and memory. We show that mice lacking EphB1, and more profoundly EphB1 and EphB2, have significantly fewer neural progenitors in the hippocampus. Furthermore, other aspects of neurogenesis, such as polarity, cell positioning, and proliferation are disrupted in animals lacking the EphB1 receptor or its cognate ephrin-B3 ligand. Our data strongly suggest that EphB1 and ephrin-B3 cooperatively regulate the proliferation and migration of neural progenitors in the hippocampus and should be added to a short list of candidate target molecules for modulating the production and integration of new neurons as a treatment for neurodegenerative diseases or brain injury. [Abstract]

Hartwick AT, Bramley JR, Yu J, Stevens KT, Allen CN, Baldridge WH, Sollars PJ, Pickard GE
Light-evoked calcium responses of isolated melanopsin-expressing retinal ganglion cells.
J Neurosci. 2007 Dec 5;27(49):13468-80.
A small number (<2%) of mammalian retinal ganglion cells express the photopigment melanopsin and are intrinsically photosensitive (ipRGCs). Light depolarizes ipRGCs and increases intracellular calcium levels ([Ca2+]i) but the signaling cascades underlying these responses have yet to be elucidated. To facilitate physiological studies on these rare photoreceptors, highly enriched ipRGC cultures from neonatal rats were generated using anti-melanopsin-mediated plate adhesion (immunopanning). This novel approach enabled experiments on isolated ipRGCs, eliminating the potential confounding influence of rod/cone-driven input. Light induced a rise in [Ca2+]i (monitored using fura-2 imaging) in the immunopanned ipRGCs and the source of this Ca2+ signal was investigated. The Ca2+ responses were inhibited by 2-aminoethoxydiphenyl borate, SKF-96365 (1-2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl-1H-imidazole), flufenamic acid, lanthanum, and gadolinium, consistent with the involvement of canonical transient receptor potential (TRP) channels in ipRGC phototransduction. However, the contribution of direct Ca2+ flux through a putative TRP channel to ipRGC [Ca2+]i was relatively small, as most (approximately 90%) of the light-induced Ca2+ responses could be blocked by preventing action potential firing with tetrodotoxin. The L-type voltage-gated Ca2+ channel (VGCC) blockers verapamil and (+)-cis-diltiazem significantly reduced the light-evoked Ca2+ responses, while the internal Ca2+ stores depleting agent thapsigargin had negligible effect. These results indicate that Ca2+ influx through VGCCs, activated after action potential firing, was the primary source for light-evoked elevations in ipRGC [Ca2+]i. Furthermore, concurrent Ca2+ imaging and cell-attached electrophysiological recordings demonstrated that the Ca2+ responses were highly correlated to spike frequency, thereby establishing a direct link between action potential firing and somatic [Ca2+]i in light-stimulated ipRGCs. [Abstract]

Villarreal DM, Gross AL, Derrick BE
Modulation of CA3 afferent inputs by novelty and theta rhythm.
J Neurosci. 2007 Dec 5;27(49):13457-67.
Models of hippocampal function suggest that the modulation of CA3 afferent input during theta rhythm allows for a rapid alternation between encoding and retrieval states, with each phase enhancing either extrinsic or intrinsic CA3 afferents, favoring either encoding or retrieval, respectively. Here, we show that during the initial exploration of a novel environment by rats, intrinsic CA3-CA3 synaptic inputs are attenuated on CA3 theta peaks, favoring extrinsic CA3 inputs, whereas extrinsic perforant path-CA3 synaptic inputs are attenuated on CA3 theta troughs, favoring intrinsic CA3 inputs. This modulation is absent when animals are re-exposed to the same environment 2 or 48 h later and thus habituates with familiarity, suggesting a process involved in learning. Modulation of CA3 synaptic inputs during novelty was blocked by atropine at a dose that blocks type 2 theta rhythm. Re-exposure to the same novel environment 48 h later in the absence of atropine did not result in habituation, but instead modulated CA3 synaptic responses as though the environment were novel and explored for the first time. The NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), administered in a dose that blocks long-term potentiation induction, did not alter CA3 synaptic modulation during initial exploration. However, like atropine, CPP blocked the habituation of synaptic modulation normally observed with re-exposure, as though the environment were novel and explored for the first time. Thus, as predicted theoretically, recurrent and cortical CA3 afferents are differentially modulated during phases of theta rhythm. This modulation is atropine sensitive and habituates in an NMDA receptor-dependent manner, suggesting an NMDA receptor-dependent process that, in conjunction with theta rhythm, contributes to encoding of novel information in the hippocampus. [Abstract]

Hall BJ, Ripley B, Ghosh A
NR2B signaling regulates the development of synaptic AMPA receptor current.
J Neurosci. 2007 Dec 5;27(49):13446-56.
The postnatal maturation of glutamatergic synapses involves a change in composition and functional contribution of postsynaptic receptors. Developing cortical synapses are dominated by NMDA receptors (NMDARs) containing NR2B subunits and are characterized by a low ratio of AMPA/NMDA receptor-mediated current. Synapse maturation is marked by the incorporation of NR2A-containing NMDA receptors and an increase in the AMPA/NMDA current ratio. We show here that NMDARs containing the NR2B subunit regulate glutamatergic transmission at developing synapses by negatively influencing the synaptic incorporation of AMPA receptors (AMPARs). Genetic removal of NR2B leads to increased surface expression and synaptic localization of AMPA receptor subunits and a corresponding increase in AMPAR-mediated synaptic current. Enrichment of synaptic AMPARs, in the absence of NR2B signaling, is associated with increased levels of transmembrane AMPAR regulatory protein (TARP) expression and is blocked by expression of a dominant-negative TARP construct (gamma-2deltaC). These observations suggest that NR2B signaling limits AMPA receptor incorporation at developing synapses by negatively regulating TARP expression and provide a mechanism to explain the maintenance of low AMPA/NMDA ratio at immature glutamatergic synapses. [Abstract]

Boccia M, Freudenthal R, Blake M, de la Fuente V, Acosta G, Baratti C, Romano A
Activation of hippocampal nuclear factor-kappaB by retrieval is required for memory reconsolidation.
J Neurosci. 2007 Dec 5;27(49):13436-45.
Initially, memory is labile and requires consolidation to become stable. However, several studies support that consolidated memories can undergo a new period of lability after retrieval. The mechanistic differences of this process, termed reconsolidation, with the consolidation process are under debate, including the participation of hippocampus. Up to this point, few reports describe molecular changes and, in particular, transcription factor (TF) involvement in memory restabilization. Increasing evidence supports the participation of the TF nuclear factor-kappaB (NF-kappaB) in memory consolidation. Here, we demonstrate that the inhibition of NF-kappaB after memory reactivation impairs retention of a hippocampal-dependent inhibitory avoidance task in mice. We used two independent disruptive strategies to reach this conclusion. First, we administered intracerebroventricular or intrahippocampal sulfasalazine, an inhibitor of IKK (IkappaB kinase), the kinase that activates NF-kappaB. Second, we infused intracerebroventricular or intrahippocampal kappaB decoy, a direct inhibitor of NF-kappaB consisting of a double-stranded DNA oligonucleotide that contains the kappaB consensus sequence. When injected immediately after memory retrieval, sulfasalazine or kappaB decoy (Decoy) impaired long-term retention. In contrast, a one base mutated kappaB decoy (mDecoy) had no effect. Furthermore, we also found NF-kappaB activation in the hippocampus, with a peak 15 min after memory retrieval. This activation was earlier than that found during consolidation. Together, these results indicate that NF-kappaB is an important transcriptional regulator in memory consolidation and reconsolidation in hippocampus, although the temporal kinetics of activation differs between the two processes. [Abstract]

Johnson AW, Crombag HS, Takamiya K, Baraban JM, Holland PC, Huganir RL, Reti IM
A selective role for neuronal activity regulated pentraxin in the processing of sensory-specific incentive value.
J Neurosci. 2007 Dec 5;27(49):13430-5.
Neuronal activity regulated pentraxin (Narp) is a secreted neuronal product which clusters AMPA receptors and regulates excitatory synaptogenesis. Although Narp is selectively enriched in brain, its role in behavior is not known. As Narp is expressed prominently in limbic regions, we examined whether Narp deletion affects performance on tasks used to assess motivational consequences of food-rewarded learning. Narp knock-out (KO) mice were unimpaired in learning simple pavlovian discriminations, instrumental lever pressing, and in acquisition of at least two aspects of pavlovian incentive learning, conditioned reinforcement and pavlovian-instrumental transfer. In contrast, Narp deletion resulted in a substantial deficit in the ability to use specific outcome expectancies to modulate instrumental performance in a devaluation task. In this task, mice were trained to respond on two levers for two different rewards. After training, mice were prefed with one of the two rewards, devaluing it. Responding on both levers was then assessed in extinction. Whereas control mice showed a significant preference in responding on the lever associated with the nondevalued reward, Narp KO mice responded equally on both levers, failing to suppress responding on the lever associated with the devalued reward. Both groups consumed more of the nondevalued reward in a subsequent choice test, indicating Narp KO mice could distinguish between the rewards themselves. These data suggest Narp has a selective role in processing sensory-specific information necessary for appropriate devaluation performance, but not in general motivational effects of reward-predictive cues on performance. [Abstract]

Li L, Bischofberger J, Jonas P
Differential gating and recruitment of P/Q-, N-, and R-type Ca2+ channels in hippocampal mossy fiber boutons.
J Neurosci. 2007 Dec 5;27(49):13420-9.
Voltage-gated Ca2+ channels in presynaptic terminals initiate the Ca2+ inflow necessary for transmitter release. At a variety of synapses, multiple Ca2+ channel subtypes are involved in synaptic transmission and plasticity. However, it is unknown whether presynaptic Ca2+ channels differ in gating properties and whether they are differentially activated by action potentials or subthreshold voltage signals. We examined Ca2+ channels in hippocampal mossy fiber boutons (MFBs) by presynaptic recording, using the selective blockers omega-agatoxin IVa, omega-conotoxin GVIa, and SNX-482 to separate P/Q-, N-, and R-type components. Nonstationary fluctuation analysis combined with blocker application revealed a single MFB contained on average approximately 2000 channels, with 66% P/Q-, 26% N-, and 8% R-type channels. Whereas both P/Q-type and N-type Ca2+ channels showed high activation threshold and rapid activation and deactivation, R-type Ca2+ channels had a lower activation threshold and slower gating kinetics. To determine the efficacy of activation of different Ca2+ channel subtypes by physiologically relevant voltage waveforms, a six-state gating model reproducing the experimental observations was developed. Action potentials activated P/Q-type Ca2+ channels with high efficacy, whereas N- and R-type channels were activated less efficiently. Action potential broadening selectively recruited N- and R-type channels, leading to an equalization of the efficacy of channel activation. In contrast, subthreshold presynaptic events activated R-type channels more efficiently than P/Q- or N-type channels. In conclusion, single MFBs coexpress multiple types of Ca2+ channels, which are activated differentially by subthreshold and suprathreshold presynaptic voltage signals. [Abstract]

Hadipour-Niktarash A, Lee CK, Desmond JE, Shadmehr R
Impairment of retention but not acquisition of a visuomotor skill through time-dependent disruption of primary motor cortex.
J Neurosci. 2007 Dec 5;27(49):13413-9.
Learning a visuomotor skill involves a distributed network which includes the primary motor cortex (M1). Despite multiple lines of evidence supporting the role of M1 in motor learning and memory, it is unclear whether M1 plays distinct roles in different aspects of learning such as acquisition and retention. Here, we investigated the nature and chronometry of that processing through a temporally specific disruption of M1 activity using single-pulse transcranial magnetic stimulation (TMS). We applied single-pulse TMS to M1 or dorsal premotor cortex (PMd) during adaptation of rapid arm movements (approximately 150 ms duration) to a visuomotor rotation. When M1 was stimulated either immediately after the end of each trial or with a 700 ms delay, subjects exhibited normal adaptation. However, whereas the memory of the subjects who received delayed-TMS showed normal rates of forgetting during deadaptation, the memory of those who received immediate TMS was more fragile: in the deadaptation period, they showed a faster rate of forgetting. Stimulation of PMd with adjusted (reduced) intensity to rule out the possibility of coactivation of this structure caused by the current spread from M1 stimulation did not affect adaptation or retention. The data suggest that, during the short time window after detection of movement errors, neural processing in M1 plays a crucial role in formation of motor memories. This processing in M1 may represent a slow component of motor memory which plays a significant role in retention. [Abstract]

Wragg RT, Hapiak V, Miller SB, Harris GP, Gray J, Komuniecki PR, Komuniecki RW
Tyramine and octopamine independently inhibit serotonin-stimulated aversive behaviors in Caenorhabditis elegans through two novel amine receptors.
J Neurosci. 2007 Dec 5;27(49):13402-12.
Biogenic amines modulate key behaviors in both vertebrates and invertebrates. In Caenorhabditis elegans, tyramine (TA) and octopamine (OA) inhibit aversive responses to 100%, but not dilute (30%) octanol. TA and OA also abolish food- and serotonin-dependent increases in responses to dilute octanol in wild-type but not tyra-3(ok325) and f14d12.6(ok371) null animals, respectively, suggesting that TA and OA modulated responses to dilute octanol are mediated by separate, previously uncharacterized, G-protein-coupled receptors. TA and OA are high-affinity ligands for TYRA-3 and F14D12.6, respectively, based on their pharmacological characterization after heterologous expression. f14d12.6::gfp is expressed in the ASHs, the neurons responsible for sensitivity to dilute octanol, and the sra-6-dependent expression of F14D12.6 in the ASHs is sufficient to rescue OA sensitivity in f14d12.6(ok371) null animals. In contrast, tyra-3::gfp appears not to be expressed in the ASHs, but instead in other neurons, including the dopaminergic CEP/ADEs. However, although dopamine (DA) also inhibits 5-HT-dependent responses to dilute octanol, TA still inhibits in dop-2; dop-1; dop-3 animals that do not respond to DA and cat-2(tm346) and Pdat-1::ICE animals that lack significant dopaminergic signaling, suggesting that DA is not an intermediate in TA inhibition. Finally, responses to TA and OA selectively desensitize after preexposure to the amines. Our data suggest that although tyraminergic and octopaminergic signaling yield identical phenotypes in these olfactory assays, they act independently through distinct receptors to modulate the ASH-mediated locomotory circuit and that C. elegans is a useful model to study the aminergic modulation of sensory-mediated locomotory behaviors. [Abstract]

Tan HY, Chen Q, Goldberg TE, Mattay VS, Meyer-Lindenberg A, Weinberger DR, Callicott JH
Catechol-O-methyltransferase Val158Met modulation of prefrontal-parietal-striatal brain systems during arithmetic and temporal transformations in working memory.
J Neurosci. 2007 Dec 5;27(49):13393-401.
Working memory (WM) is critically mediated by dopaminergic tuning of signal-to-noise in cortical neural assemblies. However, little is known about the distributed neuronal networks impacted by dopaminergic modulation in the component processes of WM. Here, we used the genotype of the Val158Met polymorphism in catechol-O-methyltransferase (COMT) as an index of relative cortical dopamine bioavailability and tuning efficiency, to examine the spatial and subprocess specificity by which dopaminergic modulation occurs within the prefrontal-parietal-striatal network during WM, thus empirically showing that dopamine plays key roles in updating and stabilizing new information at the neural systems level. In an event-related fMRI task dissociating component numerical WM subprocesses, baseline numerical size comparison engaged ventrolateral prefrontal cortical activation that correlated with COMT Val-allele load (COMT Val>Met), while performing arithmetic transformations further engaged this genotype effect in dorsolateral prefrontal cortex (DLPFC), as well as in parietal and striatal regions. Critically, additional temporal integration of information in WM disproportionately engaged greater COMT Val>Met effects only at DLPFC. COMT Val>Met effects were also observed in DLPFC during encoding of new information into WM, but not at its subsequent retrieval. Thus, temporal updating operations, but less so the retrieval of already encoded representations, engaged relatively specific dopaminergic tuning at the DLPFC. Manipulating and rapidly updating representations were sensitive to dopaminergic modulation of neural signaling in a larger prefrontal-parietal-striatal network. These findings add to the integration of dopaminergic signaling in basic cortical assemblies with their roles in specific human brain networks during the orchestration of information processing in WM. [Abstract]

Edwards CJ, Leary CJ, Rose GJ
Counting on inhibition and rate-dependent excitation in the auditory system.
J Neurosci. 2007 Dec 5;27(49):13384-92.
The intervals between acoustic elements are important in audition. Although neurons have been recorded that show interval tuning, the underlying mechanisms are unclear. The anuran auditory system is well suited for addressing this problem. One class of midbrain neurons in anurans responds selectively over a narrow range of pulse-repetition rates (PRRs) and only after several sound pulses have occurred with the "correct" timing. This "interval-counting" process can be reset by a single incorrect interval. Here we show, from whole-cell patch recordings of midbrain neurons in vivo, that these computations result from interplay between inhibition and rate-dependent excitation. An individual pulse or slowly repeated pulses elicited inhibition and subthreshold excitation. Excitation was markedly enhanced, however, when PRR was increased over a neuron-specific range. Spikes were produced when the enhanced excitation overcame the inhibition. Interval-number thresholds were positively correlated with the strength of inhibition and number of intervals required to augment the excitation. Accordingly, interval-number thresholds decreased when inhibition was attenuated by loading cells with cesium fluoride. The selectivity of these neurons for the interpulse interval, and therefore PRR, was related to the time course of excitatory events and the rate dependence of enhancement; for cells that were tuned to longer intervals, EPSPs were broader, and enhancement occurred at slower PRRs. The frequency tuning of the inhibition generally spanned that of the excitation, consistent with its role in temporal computation. These findings provide the first mechanistic understanding of interval selectivity and counting in the nervous system. [Abstract]

Vasilevko V, Xu F, Previti ML, Van Nostrand WE, Cribbs DH
Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic mice.
J Neurosci. 2007 Dec 5;27(49):13376-83.
Novel amyloid precursor protein transgenic mice, which contain the Swedish as well as the vasculotropic Dutch and Iowa mutations (Tg-SwDI), were used to investigate the mechanisms of antibody-mediated clearance of amyloid-beta (Abeta) from the brain. Export of the Abeta-DI peptide across the blood-brain barrier is severely reduced because of the vasculotropic mutations. Therefore, antibody-mediated clearance of Abeta-DI is dependent on antibodies entering the brain. In this report, we immunized Tg-SwDI mice with various peptide antigens, including Abeta40-DI, Abeta42, and an Abeta epitope vaccine. Immunization of Tg-SwDI mice with substantial cortical diffuse and vascular fibrillar deposits failed to promote clearance of parenchymal or vascular amyloid deposits. We then immunized young Tg-SwDI mice before the accumulation of Abeta and saw no evidence that anti-Abeta antibodies could diminish deposition of parenchymal or vascular amyloid deposits. However, injection of anti-Abeta antibodies, affinity-purified from immunized Tg-SwDI mice, into the hippocampus induced a rapid clearance of diffuse Abeta deposits but not vascular amyloid deposits. These results further support the "peripheral sink hypothesis" as a legitimate mechanism of antibody-mediated clearance of Abeta when the blood-brain barrier remains intact. Thus, approaches that deliver immunotherapy to the brain may be more effective at clearing Abeta than immunization strategies in which the majority of the antibodies are in the periphery. [Abstract]

Horvath MC, Kovacs GG, Kovari V, Majtenyi K, Hurd YL, Keller E
Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age.
J Neurosci. 2007 Dec 5;27(49):13371-5.
Dysfunction of mesocorticolimbic dopaminergic neurons is considered a common feature of all drugs of abuse, yet few investigations have evaluated the dopamine (DA) system in nonstimulant human abusers. We examined mRNA expression levels of DA transporter (DAT), tyrosine hydroxylase (TH), dopamine D2 receptor, alpha-synuclein, and nuclear receptor-related 1 (Nurr1) in discrete mesocorticolimbic and nigrostriatal subpopulations of heroin users and control subjects. The chronic use of heroin was significantly associated with decreased DAT mRNA expression localized to the paranigral nucleus (PN) and the mesolimbic division of the ventral tegmental area (VTA) with no alterations in nigrostriatal populations. Consistently, the density of DAT immunoreactivity was significantly reduced in the nucleus accumbens but not in dorsal striatum, mesolimbic and nigrostriatal efferent targets, respectively. Significant alteration of the mRNA expression of Nurr1, a transcription factor that regulates DAT expression, was also confined to the PN. Moreover, the results revealed an exaggerated reduction of Nurr1 expression with age in heroin users (r = -0.8268, p < 0.001 vs controls, r = -0.6204, p = 0.0746). TH and alpha-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D2 receptor. Evaluating midbrain mu- and kappa-opioid receptors, relevant for the action of heroin and regulation of DA neurons, revealed dysregulation of G-protein coupling selective to the VTA PN. Altogether the current findings provide direct neurobiological evidence that midbrain reward circuits have the most prominent DA and opioid impairments in human heroin abusers and that abnormal Nurr1 transcription with opiate use may exacerbate limbic dysfunction with age. [Abstract]

Moreira FA
Serotonin, the prefrontal cortex, and the antidepressant-like effect of cannabinoids.
J Neurosci. 2007 Dec 5;27(49):13369-70. [Abstract]

Maus GW
Swimming with and against the stream: does motor adaptation to lateral forces influence visual motion perception?
J Neurosci. 2007 Dec 5;27(49):13367-8. [Abstract]

Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, LaFerla FM, Pike CJ
Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice.
J Neurosci. 2007 Nov 28;27(48):13357-65.
Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormone therapy may reduce this risk. However, the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on beta-amyloid (Abeta) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Abeta accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Abeta accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women. [Abstract]

Aragona BJ, Wang Z
Opposing regulation of pair bond formation by cAMP signaling within the nucleus accumbens shell.
J Neurosci. 2007 Nov 28;27(48):13352-6.
The formation of monogamous pair bonds, by prairie voles, is facilitated by activation of dopamine (DA) D2-like, but not D1-like, receptors within the nucleus accumbens (NAcc) shell. Because DA exerts opposing regulation of cAMP production depending on the subtype of receptor activated, we tested the hypothesis that DA regulation of pair bond formation is mediated via the cAMP signaling cascade. Consistent with activation of D2-like receptors, decreasing cAMP signaling, by blocking cAMP binding sites on protein kinase A (PKA), facilitated partner preference formation. Conversely, increasing cAMP signaling, by preventing the activation of inhibitory G-proteins, activating stimulatory G-proteins, or stimulating PKA prevented the formation of mating-induced partner preferences. These manipulations were effective in the shell, but not the core, of the NAcc. Together, these data demonstrate opposing regulation over pair bond formation by cAMP signaling within the NAcc shell. [Abstract]

Saliba RS, Michels G, Jacob TC, Pangalos MN, Moss SJ
Activity-dependent ubiquitination of GABA(A) receptors regulates their accumulation at synaptic sites.
J Neurosci. 2007 Nov 28;27(48):13341-51.
GABA(A) receptors (GABA(A)Rs) are the major mediators of fast synaptic inhibition in the brain. In neurons, these receptors undergo significant rates of endocytosis and exocytosis, processes that regulate both their accumulation at synaptic sites and the efficacy of synaptic inhibition. Here we have evaluated the role that neuronal activity plays in regulating the residence time of GABA(A)Rs on the plasma membrane and their targeting to synapses. Chronic blockade of neuronal activity dramatically increases the level of the GABA(A)R ubiquitination, decreasing their cell surface stability via a mechanism dependent on the activity of the proteasome. Coincident with this loss of cell surface expression levels, TTX treatment reduced both the amplitude and frequency of miniature inhibitory synaptic currents. Conversely, increasing the level of neuronal activity decreases GABA(A)R ubiquitination enhancing their stability on the plasma membrane. Activity-dependent ubiquitination primarily acts to reduce GABA(A)R stability within the endoplasmic reticulum and, thereby, their insertion into the plasma membrane and subsequent accumulation at synaptic sites. Thus, activity-dependent ubiquitination of GABA(A)Rs and their subsequent proteasomal degradation may represent a potent mechanism to regulate the efficacy of synaptic inhibition and may also contribute to homeostatic synaptic plasticity. [Abstract]

Kang HJ, Adams DH, Simen A, Simen BB, Rajkowska G, Stockmeier CA, Overholser JC, Meltzer HY, Jurjus GJ, Konick LC, Newton SS, Duman RS
Gene expression profiling in postmortem prefrontal cortex of major depressive disorder.
J Neurosci. 2007 Nov 28;27(48):13329-40.
Investigations of the molecular mechanisms underlying major depressive disorder (MDD) have been hampered by the complexity of brain tissue and sensitivity of gene expression profiling approaches. To address these issues, we used discrete microdissections of postmortem dorsolateral prefrontal cortex (DLPFC) (area 9) and an oligonucleotide (60mer) microarray hybridization procedure that increases sensitivity without RNA amplification. Mixed-effects statistical methods were used to rigorously control for medication usage in the subset of medicated depressed subjects. These analyses yielded a rich profile of dysregulated genes. Two of the most highly dysregulated genes of interest were stresscopin, a neuropeptide involved in stress responses, and Forkhead box D3 (FOXD3), a transcription factor. Secondary cell-based analysis demonstrated that stresscopin and FoxD3 are increased in neurons of DLPFC gray matter of MDD subjects. These findings identify abnormal gene expression in a discrete region of MDD subjects and contribute to further elucidation of the molecular alterations of this complex mood disorder. [Abstract]

Kerr JN, de Kock CP, Greenberg DS, Bruno RM, Sakmann B, Helmchen F
Spatial organization of neuronal population responses in layer 2/3 of rat barrel cortex.
J Neurosci. 2007 Nov 28;27(48):13316-28.
Individual pyramidal neurons of neocortex show sparse and variable responses to sensory stimuli in vivo. It has remained unclear how this variability extends to population responses on a trial-to-trial basis. Here, we characterized single-neuron and population responses to whisker stimulation in layer 2/3 (L2/3) of identified columns in rat barrel cortex using in vivo two-photon calcium imaging. Optical detection of single action potentials from evoked calcium transients revealed low spontaneous firing rates (0.25 Hz), variable response probabilities (range, 0-0.5; mean, 0.2 inside barrel column), and weak angular tuning of L2/3 neurons. On average, both the single-neuron response probability and the percentage of the local population activated were higher in the barrel column than above septa or in neighboring columns. Within the barrel column, mean response probability was highest in the center (0.4) and declined toward the barrel border. Neuronal pairs showed correlations in both spontaneous and sensory-evoked activity that depended on the location of the neurons. Correlation decreased with increasing distance between neurons and, for neuronal pairs the same distance apart, with distance of the pair from the barrel column center. Although neurons are therefore not activated independently from each other, we did not observe precisely repeating spatial activation patterns. Instead, population responses showed large trial-to-trial variability. Nevertheless, the accuracy of decoding stimulus onset times from local population activity increased with population size and depended on anatomical location. We conclude that, despite their sparseness and variability, L2/3 population responses show a clear spatial organization on the columnar scale. [Abstract]

Brown TC, Correia SS, Petrok CN, Esteban JA
Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation.
J Neurosci. 2007 Nov 28;27(48):13311-5.
Endosomal membrane trafficking in dendritic spines is important for proper synaptic function and plasticity. However, little is known about the molecular identity and functional compartmentalization of the membrane trafficking machinery operating at the postsynaptic terminal. Here we report that the transport of AMPA-type glutamate receptors into synapses occurs in two discrete steps, and we identify the specific endosomal functions that control this process during long-term potentiation. We found that Rab11-dependent endosomes translocate AMPA receptors from the dendritic shaft into spines. Subsequently, an additional endosomal trafficking step, controlled by Rab8, drives receptor insertion into the synaptic membrane. Separate from this receptor delivery route, we show that Rab4 mediates a constitutive endosomal recycling within the spine. This Rab4-dependent cycling is critical for maintaining spine size but does not influence receptor transport. Therefore, our data reveal a highly compartmentalized endosomal network within the spine and identify the molecular components and functional organization of the membrane organelles that mediate AMPA receptor synaptic delivery during plasticity. [Abstract]

Rowe JB, Sakai K, Lund TE, Rams�y T, Christensen MS, Baare WF, Paulson OB, Passingham RE
Is the prefrontal cortex necessary for establishing cognitive sets?
J Neurosci. 2007 Nov 28;27(48):13303-10.
There is evidence from neuroimaging that the prefrontal cortex may be involved in establishing task set activity in advance of presentation of the task itself. To find out whether it plays an essential role, we examined patients with unilateral lesions of the rostral prefrontal cortex. They were first instructed as to whether to perform a spatial or a verbal working memory task and then given spatial and verbal items after a delay of 4-12 s. The patients showed an increase in switch costs, making more errors by repeating what they had done on the previous trial. They were able to establish regional task set activity during the instruction delay, as evidenced by sustained changes in the blood oxygenation level-dependent signal in caudal frontal regions. However, in contrast to healthy controls, they were less able to maintain functional connectivity among the surviving task-related brain regions, as evidenced by reduced correlations between them during instruction delays. The results suggest that the left rostral prefrontal cortex is indeed required for establishing a cognitive set but that the essential function is to support the functional connectivity among the task-related regions. [Abstract]