The Neuroscientist recent issues

The Neuroscientist Comments

Tue, 13 Oct 2009 18:01:50 PDT

Perspectives on Neuroscience and Behavior

Tue, 13 Oct 2009 18:01:50 PDT

Disease Mechanisms in Neuroscience

Tue, 13 Oct 2009 18:01:50 PDT

Where Are the Human Speech and Voice Regions, and Do Other Animals Have Anything Like Them?

Petkov, C. I., Logothetis, N. K., Obleser, J. — Tue, 13 Oct 2009 18:01:50 PDT

Modern lesion and imaging work in humans has been clarifying which brain regions are involved in the processing of speech and language. Concurrently, some of this work has aimed to bridge the gap to the seemingly incompatible evidence for multiple brain-processing pathways that first accumulated in nonhuman primates. For instance, the idea of a posterior temporal-parietal "Wernicke’s" territory, which is thought to be instrumental for speech comprehension, conflicts with this region of the brain belonging to a spatial "where" pathway. At the same time a posterior speech-comprehension region ignores the anterior temporal lobe and its "what" pathway for evaluating the complex features of sensory input. Recent language models confirm that the posterior or dorsal stream has an important role in human communication, by a reconceptualization of the "where" into a "how-to" pathway with a connection to the motor system for speech comprehension. Others have tried to directly implicate the "what" pathway for speech comprehension, relying on the growing evidence in humans for anterior-temporal involvement in speech and voice processing. Coming full circle, we find that the recent imaging of vocalization and voice preferring regions in nonhuman primates allows us to make direct links to the human imaging data involving the anterior-temporal regions. The authors describe how comparison of the structure and function of the vocal communication system of humans and other animals is clarifying evolutionary relationships and the extent to which different species can model human brain function.

Synaptic Protein Degradation as a Mechanism in Memory Reorganization

Kaang, B.-K., Lee, S.-H., Kim, H. — Tue, 13 Oct 2009 18:01:50 PDT

An accumulating body of evidence shows that reactivated long-term memory undergoes a dynamic process called reconsolidation, in which de novo protein synthesis is required to maintain the memory. These findings open up a new dimension in the field of memory research. However, few studies have shown how once-consolidated memory becomes labile. The authors’ recent findings have demonstrated that pre-existing long-term memory becomes unstable via the ubiquitin/ proteasome-dependent protein degradation pathway and that this labile state is required for the reorganization of fear memory. Here, the authors review this finding and focus on the labile state that is critical for the reorganization of memory triggered after memory retrieval.

Compensatory Changes at the Cerebral Cortical Level after Spinal Cord Injury

Nishimura, Y., Isa, T. — Tue, 13 Oct 2009 18:01:50 PDT

Neurorehabilitation is based on the concept that rehabilitative training recruits neuronal systems that remain intact after the brain and/or spinal cord injury to take over the impaired function. Understanding the neural mechanism of recovery will surely contribute to the development of evidence-based rehabilitation therapies. Recent studies have shown that after a lesion of the lateral corticospinal tract at midcervical segments, the remaining pathways can compensate for finger dexterity in macaque monkeys in a few weeks to months. Combined brain imaging and reversible pharmacological inactivation of motor cortical regions suggested that the recovery involves the bilateral primary motor cortex during the early recovery stage and more extensive regions of the contralesional primary motor cortex and bilateral premotor cortex during the late stage. Thus, contribution of each cortical region changes depending on the recovery stage, suggesting that the brain uses available pre-existing neural systems by reducing inhibition during the early stage and enhances the original systems or recruits other systems by plastic change of the neural circuits during the late stage. These changes in the activation pattern of motor-related areas represent an adaptive strategy for functional compensation after spinal cord injury.

Face Processing: The Interplay of Nature and Nurture

Park, J., Newman, L. I., Polk, T. A. — Tue, 13 Oct 2009 18:01:50 PDT

A number of behavioral and neuroscientific studies suggest that face processing is qualitatively different from the processing of other visual stimuli. Why? Is face processing in some sense innate? What role does experience play in the development of face processing? The authors review recent evidence related to these questions. They begin by identifying some of the ways in which face processing is special. They then consider findings that demonstrate a crucial role for experience-independent genetic mechanisms in the development of face processing and its neural substrates. Finally, the authors review studies demonstrating the crucial role played by experience-dependent mechanisms. These findings support the hypothesis that there is a genetic predisposition for a special face processing mechanism, but that experience plays a crucial role in tuning this mechanism during development.

Gliopathic Pain: When Satellite Glial Cells Go Bad

Tue, 13 Oct 2009 18:01:50 PDT

Neurons in sensory ganglia are surrounded by satellite glial cells (SGCs) that perform similar functions to the glia found in the CNS. When primary sensory neurons are injured, the surrounding SGCs undergo characteristic changes. There is good evidence that the SGCs are not just bystanders to the injury but play an active role in the initiation and maintenance of neuronal changes that underlie neuropathic pain. In this article the authors review the literature on the relationship between SGCs and nociception and present evidence that changes in SGC potassium ion buffering capacity and glutamate recycling can lead to neuropathic pain-like behavior in animal models. The role that SGCs play in the immune responses to injury is also considered. We propose the term gliopathic pain to describe those conditions in which central or peripheral glia are thought to be the principal generators of principal pain generators.

Spine Modifications Associated with Long-Term Potentiation

Yang, Y., Zhou, Q. — Tue, 13 Oct 2009 18:01:50 PDT

Modification of neuronal connections is essential for the development of the nervous system and learning and memory functions of the mature brain. Structural modifications, such as modification of dendritic spines where the modified synapses reside, accompany and may even be required for these functional modifications. Recent advances in fluorescence microscopy, coupled with molecular approaches, prompted a rapid advance in the authors’ understanding of spine remodeling associated with synaptic plasticity, especially long-term potentiation. In this article, they review recent progress in this field, with focus on the potential functions of spine remodeling and key issues to be resolved.

Brain Clocks: From the Suprachiasmatic Nuclei to a Cerebral Network

Mendoza, J., Challet, E. — Tue, 13 Oct 2009 18:01:50 PDT

Circadian timing affects almost all life’s processes. It not only dictates when we sleep, but also keeps every cell and tissue working under a tight temporal regimen. The daily variations of physiology and behavior are controlled by a highly complex system comprising of a master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus, extra-SCN cerebral clocks, and peripheral oscillators. Here are presented similarities and differences in the molecular mechanisms of the clock machinery between the primary SCN clock and extra-SCN brain clocks. Diversity of secondary clocks in the brain, their specific sensitivities to time-giving cues, as their differential coupling to the master SCN clock, may allow more plasticity in the ability of the circadian timing system to integrate a wide range of temporal information. Furthermore, it raises the possibility that pathophysiological alterations of internal timing that are deleterious for health may result from internal desynchronization within the network of cerebral clocks.

The Noninvasive Dissection of the Human Visual Cortex: Using fMRI and TMS to Study the Organization of the Visual Brain

McKeefry, D. J., Gouws, A., Burton, M. P., Morland, A. B. — Tue, 13 Oct 2009 18:01:50 PDT

The development of brain imaging techniques, such as fMRI, has given modern neuroscientists unparalleled access to the inner workings of the living human brain. Visual processing in particular has proven to be particularly amenable to study with fMRI. Studies using this technique have revealed the existence of multiple representations of visual space with differing functional roles across many cortical locations. Yet, although fMRI provides an excellent means by which we can localize and map different areas across the visual brain, it is less well suited to providing information as to whether activation within a particular cortical region is directly related to perception or behavior. These kinds of causal links can be made, however, when fMRI is combined with transcranial magnetic stimulation (TMS). TMS is a noninvasive technique that can bring about localized, transient disruption of cortical function and can induce functional impairments in the performance of specific tasks. When guided by the detailed localizing and mapping capabilities of fMRI, TMS can be used as a means by which the functional roles of different visual areas can be investigated. This review highlights recent insights that the techniques of fMRI and TMS have given us with regard to the function and contributions of the many different visual areas to human visual perception.

Remapping the Somatosensory Cortex after Stroke: Insight from Imaging the Synapse to Network

Winship, I. R., Murphy, T. H. — Tue, 13 Oct 2009 18:01:50 PDT

Together, thousands of neurons with similar function make up topographically oriented sensory cortex maps that represent contralateral body parts. Although this is an accepted model for the adult cortex, whether these same rules hold after stroke-induced damage is unclear. After stroke, sensory representations damaged by stroke remap onto nearby surviving neurons. Here, we review the process of sensory remapping after stroke at multiple levels ranging from the initial damage to synapses, to their rewiring and function in intact sensory circuits. We introduce a new approach using in vivo 2-photon calcium imaging to determine how the response properties of individual somatosensory cortex neurons are altered during remapping. One month after forelimb-area stroke, normally highly limb-selective neurons in surviving peri-infarct areas exhibit remarkable flexibility and begin to process sensory stimuli from multiple limbs as remapping proceeds. Two months after stroke, neurons within remapped regions develop a stronger response preference. Thus, remapping is initiated by surviving neurons adopting new roles in addition to their usual function. Later in recovery, these remapped forelimb-responsive neurons become more selective, but their new topographical representation may encroach on map territories of neurons that process sensory stimuli from other body parts. Neurons responding to multiple limbs may reflect a transitory phase in the progression from their involvement in one sensorimotor function to a new function that replaces processing lost due to stroke.

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology and Therapeutics of Mood Disorders

Machado-Vieira, R., Manji, H. K., Zarate, C. A. — Tue, 13 Oct 2009 18:01:50 PDT

Bipolar disorder and major depressive disorder are common, chronic, and recurrent mood disorders that affect the lives of millions of individuals worldwide. Growing evidence suggests that glutamatergic system dysfunction is directly involved in mood disorders. This article describes the role of the "tripartite glutamatergic synapse," comprising presynaptic and postsynaptic neurons and glial cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic neurons and glia directly control synaptic and extrasynaptic glutamate levels/ release through integrative effects that target glutamate excitatory amino acid transporters, postsynaptic density proteins, ionotropic receptors (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], N-methyl-D-aspartate [NMDA], and kainate), and metabotropic receptors. This article also explores the glutamatergic modulators riluzole and ketamine, which are considered valuable proof-of-concept agents for developing the next generation of antidepressants and mood stabilizers. In therapeutically relevant paradigms, ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and riluzole preferentially targets presynaptic voltage-operated channels and glia.

Posttraumatic Stress Disorder: The Role of Medial Prefrontal Cortex and Amygdala

Koenigs, M., Grafman, J. — Tue, 13 Oct 2009 18:01:50 PDT

Posttraumatic stress disorder (PTSD) is characterized by recurrent distressing memories of an emotionally traumatic event. In this review, the authors present neuroscientific data highlighting the function of two brain areas—the amygdala and ventromedial prefrontal cortex (vmPFC)—in PTSD and related emotional processes. A convergent body of human and nonhuman studies suggests that the amygdala mediates the acquisition and expression of conditioned fear and the enhancement of emotional memory, whereas the vmPFC mediates the extinction of conditioned fear and the volitional regulation of negative emotion. It has been theorized that the vmPFC exerts inhibition on the amygdala, and that a defect in this inhibition could account for the symptoms of PTSD. This theory is supported by functional imaging studies of PTSD patients, who exhibit hypoactivity in the vmPFC but hyperactivity in the amygdala. A recent study of brain-injured and trauma-exposed combat veterans confirms that amygdala damage reduces the likelihood of developing PTSD. But contrary to the prediction of the top-down inhibition model, vmPFC damage also reduces the likelihood of developing PTSD. The putative roles of the amygdala and the vmPFC in the pathophysiology of PTSD, as well as implications for potential treatments, are discussed in light of these results.

The State of Synapses in Fragile X Syndrome

Pfeiffer, B. E., Huber, K. M. — Tue, 13 Oct 2009 18:01:50 PDT

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading genetic cause of autism. There is increasing evidence in both FXS and other forms of autism that alterations in synapse number, structure, and function are associated and contribute to these prevalent diseases. FXS is caused by loss of function of the Fmr1 gene, which encodes the RNA binding protein, fragile X mental retardation protein (FMRP). Therefore, FXS is a tractable model to understand synaptic dysfunction in cognitive disorders. FMRP is present at synapses where it associates with mRNA and polyribosomes. Accumulating evidence finds roles for FMRP in synapse development, elimination, and plasticity. Here, the authors review the synaptic changes observed in FXS and try to relate these changes to what is known about the molecular function of FMRP. Recent advances in the understanding of the molecular and synaptic function of FMRP, as well as the consequences of its loss, have led to the development of novel therapeutic strategies for FXS.

The Neuroscientist Comments

Fri, 07 Aug 2009 17:44:18 PDT

Perspectives on Neuroscience and Behavior

Fri, 07 Aug 2009 17:44:18 PDT

AMP-Activated Protein Kinase (AMPK) Molecular Crossroad for Metabolic Control and Survival of Neurons

Spasic, M. R., Callaerts, P., Norga, K. K. — Fri, 07 Aug 2009 17:44:18 PDT

AMP-activated protein kinase (AMPK) constitutes a molecular hub for cellular metabolic control, common to all eukaryotic cells. Numerous reports have established how AMPK responds to changes in the AMP:ATP ratio as a measure of cellular energy levels. In this way, it integrates control over a number of metabolic enzymes and adapts cellular processes to the current energy status in various cell types, such as muscle and liver cells. The role of AMPK in the development, function, and maintenance of the nervous system, on the other hand, has only recently gained attention. Neurons, while highly metabolically active, have poor capacity for nutrient storage and are thus sensitive to energy fluctuations. Recent reports demonstrate that AMPK may have neuroprotective properties and is activated in neurons by resveratrol but also by metabolic stress in the form of ischemia/hypoxia and glucose deprivation. Novel studies on AMPK also implicate neuronal activity as a critical factor in neurodegeneration. Here we discuss the latest advances in the knowledge of AMPK's role in the metabolic control and survival of excitable cells.

The Role of the p75 Neurotrophin Receptor in Cholinergic Dysfunction in Alzheimer's Disease

Coulson, E.J., May, L.M., Sykes, A.M., Hamlin, A.S. — Fri, 07 Aug 2009 17:44:18 PDT

Degeneration of basal forebrain cholinergic neurons is a common feature of Alzheimer's disease and is proposed to be an early and key event in the condition's etiology. This review discusses recent findings that strongly link the p75 neurotrophin receptor (p75^NTR) to both cholinergic neuron degeneration and the production of toxic forms of amyloid-beta (Aß), which is found deposited as amyloid plaques in the brains of Alzheimer's disease patients. Although elucidating the underlying molecular mechanisms and the clinical significance of these findings will require further experimentation, a number of possible scenarios and future research directions are presented.

Is Progesterone a Candidate Neuroprotective Factor for Treatment following Ischemic Stroke?

Gibson, C. L, Coomber, B., Rathbone, J. — Fri, 07 Aug 2009 17:44:18 PDT

Gender differences in stroke outcome have implicated steroid hormones as potential neuroprotective candidates. However, no clinical trials examining hormone replacement therapy on outcome following ischemic stroke have investigated the effect of progesterone-only treatment. In this review the authors examine the experimental evidence for the neuroprotective potential of progesterone and give an insight into potential mechanisms of action following ischemic stroke. To date, 17 experimental studies have investigated the neuroprotective potential of progesterone for ischemic stroke in terms of ability to both reduce cell loss and increase functional outcome. Of these 17 published studies the majority reported a beneficial effect with three studies reporting a nil effect and only one study reporting a negative effect. However, there are important issues that the authors address in this review in terms of the methodological quality of studies in relation to the STAIR recommendations. In terms of the proposed mechanisms of progesterone neuroprotection we show that progesterone is versatile and acts at multiple targets to facilitate neuronal survival and minimize cell damage and loss. A large amount of experimental evidence indicates that progesterone is a neuroprotective candidate for ischemic stroke; however, to progress to clinical trial a number of key experimental studies remain outstanding.

Neuronal Networks in Alzheimer's Disease

Yong He, , Zhang Chen, , Gaolang Gong, , Evans, A. — Fri, 07 Aug 2009 17:44:18 PDT

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that can be clinically characterized by impaired memory and many other cognitive functions. Previous studies have demonstrated that the impairment is accompanied by not only regional brain abnormalities but also changes in neuronal connectivity between anatomically distinct brain regions. Specifically, using neurophysiological and neuroimaging techniques as well as advanced graph theory—based computational approaches, several recent studies have suggested that AD patients have disruptive neuronal integrity in large-scale structural and functional brain systems underlying high-level cognition, as demonstrated by a loss of small-world network characteristics. Small world is an attractive model for the description of complex brain networks because it can support both segregated and integrated information processing. The altered small-world organization thus reflects aberrant neuronal connectivity in the AD brain that is most likely to explain cognitive deficits caused by this disease. In this review, we will summarize recent advances in the brain network research on AD, focusing mainly on the large-scale structural and functional descriptions. The literature reviewed here suggests that AD patients are associated with integrative abnormalities in the distributed neuronal networks, which could provide new insights into the disease mechanism in AD and help us to uncover an imaging-based biomarker for the diagnosis and monitoring of the disease.

The Barrel Cortex as a Model to Study Dynamic Neuroglial Interaction

Giaume, C., Maravall, M., Welker, E., Bonvento, G. — Fri, 07 Aug 2009 17:44:18 PDT

There is increasing evidence that glial cells, in particular astrocytes, interact dynamically with neurons. The well-known anatomofunctional organization of neurons in the barrel cortex offers a suitable and promising model to study such neuroglial interaction. This review summarizes and discusses recent in vitro as well as in vivo works demonstrating that astrocytes receive, integrate, and respond to neuronal signals. In addition, they are active elements of brain metabolism and exhibit a certain degree of plasticity that affects neuronal activity. Altogether these findings indicate that the barrel cortex presents glial compartments overlapping and interacting with neuronal compartments and that these properties help define barrels as functional and independent units. Finally, this review outlines how the use of the barrel cortex as a model might in the future help to address important questions related to dynamic neuroglia interaction.

Peroxisomes, Myelination, and Axonal Integrity in the CNS

Baes, M., Aubourg, P. — Fri, 07 Aug 2009 17:44:18 PDT

Peroxisomes are ubiquitous organelles with multiple metabolic functions, but their precise role in the maintenance of tissues is not well understood. All diseases caused by partial or complete peroxisome dysfunction are characterized by a variety of neurological abnormalities, underscoring the importance of peroxisomes in nervous tissue. The interrelationship between metabolic abnormalities, histological changes, and clinical signs in these peroxisomal diseases has not yet been clarified. During the past decade, a more systematic study of the consequences of peroxisome dysfunction was possible through the generation of knockout mice with generalized or conditional inactivation of peroxisomal proteins. It appears that peroxisomes are necessary for the preservation of axonal integrity and for the formation and maintenance of myelin.

The Role of Ribbons at Sensory Synapses

LoGiudice, L., Matthews, G. — Fri, 07 Aug 2009 17:44:18 PDT

Synaptic ribbons are organelles that tether vesicles at the presynaptic active zones of sensory neurons in the visual, auditory, and vestibular systems. These neurons generate sustained, graded electrical signals in response to sensory stimuli, and fidelity of transmission therefore requires their synapses to release neurotransmitter continuously at high rates. It has long been thought that the ribbons at the active zones of sensory synapses accomplish this task by enhancing the size and accessibility of the readily releasable pool of synaptic vesicles, which may represent the vesicles attached to the ribbon. Recent evidence suggests that synaptic ribbons immobilize vesicles in the resting cell and coordinate the transient, synchronous release of vesicles in response to stimulation, but it is not yet clear how the ribbon can efficiently mobilize and coordinate multiple vesicles for release. However, detailed anatomical, electrophysiological, and optical studies have begun to reveal the mechanics of release at ribbon synapses, and this multidisciplinary approach promises to reconcile structure, function, and mechanism at these important sensory synapses.

Lipid Mediators in the Neural Cell Nucleus: Their Metabolism, Signaling, and Association with Neurological Disorders

Farooqui, A. A. — Fri, 07 Aug 2009 17:44:18 PDT

Lipid mediators are important endogenous regulators of neural cell proliferation, differentiation, oxidative stress, inflammation, and apoptosis. They originate from enzymic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. Arachidonic acid-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of cell proliferation, differentiation, oxidative stress, and neuroinflammation. Another arachidonic acid-derived lipid mediator is lipoxin. Eicosanoids have proinflammatory effects, whereas lipoxins produce antiinflammatrory effects. The crossponding lipid mediators of docosahexaenoic acid metabolism are named docosanoids. They include resolvins, protectins, and neuroprotectins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in the brain tissue. Other glycerophospholipid-derived lipid mediators are platelet-activating factor, lysophosphatidic acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators. Sphingolipid-derived lipid mediators are ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. They mediate cellular differentiation, cell growth, and apoptosis. Similarly, cholesterol-derived lipid mediators hydroxycholesterol and oxycholesterol produce apoptosis. Most of these mediators originate from the plasma membrane. The nucleus has its own set of enzymes and lipid mediators that originate from the nuclear envelope and matrix. The purpose of this commentary is to describe basic and clinical information on lipid mediators in the nucleus.

The Neuroscientist Comments

Tue, 12 May 2009 18:01:39 PDT

Perspectives on Neuroscience and Behavior

Tue, 12 May 2009 18:01:39 PDT

Disease Mechanisms in Neuroscience

Tue, 12 May 2009 18:01:39 PDT

GABA Vesicles at Synapses: Are There 2 Distinct Pools?

Hablitz, J. J., Mathew, S. S., Pozzo-Miller, L. — Tue, 12 May 2009 18:01:39 PDT

Fast synaptic inhibition in the neocortex is mediated by the neurotransmitter GABA, acting on GABA_A receptors. Neurotransmitters, including GABA, are stored in synaptic vesicles at presynaptic nerve terminals. A long-held assumption has been that evoked and spontaneous neurotransmissions draw on the same pools of vesicles. We review the evidence from FM1-43 studies supporting the contention that at least 2 distinct pools of GABA vesicles are present at inhibitory synapses in the rat neocortex. FM1-43 uptake during spontaneous vesicle endocytosis labels a vesicle pool within neocortical inhibitory nerve terminals that is released much more slowly ("reluctant" pool) than those vesicles loaded by electrical stimulation of afferent fibers or hyperkalemic solutions. These multiple pools may play diverse roles in such processes as long-term depression and/or potentiating of inhibitory synaptic transmission, homeostatic plasticity of inhibitory activity, or developmental changes in inhibitory synaptic transmission.

Degenerate T-Cell Receptor Recognition, Autoreactive Cells, and the Autoimmune Response in Multiple Sclerosis

Markovic-Plese, S. — Tue, 12 May 2009 18:01:39 PDT

Multiple sclerosis (MS) is the leading cause of disability in the young adult population. While the immunopathogenetic mechanisms that drive the disease have been extensively studied, the autoantigens that trigger the chronic central nervous system inflammation are still not identified. Flexibility/ degeneracy of the T-cell receptor (TCR) in antigen recognition could have a physiological role in thymic selection and the development of comprehensive TCR repertoire and protection from infections. Here, the author explores the possibility that such flexibility/degeneracy may also play a role in the induction of autoimmune diseases. Major histocompatibility complex (MHC) class II alleles of the DR2 haplotype DR2a (DRB5*0101) and DR2b (DRB1*1501) are genes associated with an increased risk for MS in Caucasian populations. Peptide binding to the MHC molecule is a prerequisite for recognition by TCRs, whereby the CD4+ T-cell response is restricted by specific MHC class II DR molecules. To selectively expand and characterize DR2-restricted T-cells with degenerate TCR (TCR_deg), the authors designed MHC class II DR2-anchored peptide mixtures, which preferentially bind to the DR2a and DR2b antigen-presenting molecules. Peptides in these mixtures have specific amino acids in the DR2 binding positions but have randomized amino acids at all other positions of the peptide. Due to the low concentration of individual peptides in these mixtures/libraries, the authors assume that only T-cells with TCR_deg will proliferate in response to these mixtures. The authors have recently identified an increased DR2 restricted TCR_deg T-cell frequency in MS patients in comparison to healthy controls, their cross-reactivity to myelin basic protein, and the secretion of proinflammatory cytokines, all of which suggest that these cells may play a role in the development of the autoimmune response in MS.

The Predictive Brain State: Asynchrony in Disorders of Attention?

Ghajar, J., Ivry, R. B. — Tue, 12 May 2009 18:01:39 PDT

It is postulated that a key function of attention in goal-oriented behavior is to reduce performance variability by generating anticipatory neural activity that can be synchronized with expected sensory information. A network encompassing the prefrontal cortex, parietal lobe, and cerebellum may be critical in the maintenance and timing of such predictive neural activity. Dysfunction of this temporal process may constitute a fundamental defect in attention, causing working memory problems, distractibility, and decreased awareness.

The Role of the Ubiquitin Proteasome System in Ischemia and Ischemic Tolerance

Meller, R. — Tue, 12 May 2009 18:01:39 PDT

Ubiquitin modification targets a protein for rapid degradation by the proteasome. However, polyubiquitination of proteins can result in multiple functions depending on the topology of the ubiquitin chain. Therefore, ubiquitin signaling offers a more complex and versatile biology compared with many other posttranslational modifications. One area of potential for the application of this knowledge is the field of ischemia-induced brain damage, as occurs following a stroke. The ubiquitin proteasome system may exert a dual role on neuronal outcome following ischemia. Harmful ischemia results in an overload of the ubiquitin proteasome system, and blocking the proteasome reduces brain infarction following ischemia. However, the rapid and selective degradation of proteins following brief ischemia results in endogenous protection against ischemia. Therefore, further understanding of the molecular signaling mechanisms that regulate the ubiquitin proteasome system may reveal novel therapeutic targets to reduce brain damage when ischemia is predicted or reduce the activation of the cell death mechanisms and the inflammatory response following stroke. The aim of this review is to discuss some of the recent advances in the understanding of protein ubiquitination and its implications for novel stroke therapies.

How Humans Count: Numerosity and the Parietal Cortex

Piazza, M., Izard, V. — Tue, 12 May 2009 18:01:39 PDT

Numerosity (the number of objects in a set), like color or movement, is a basic property of the environment. Animal and human brains have been endowed by evolution by mechanisms based on parietal circuitry for representing numerosity in an highly abstract, although approximate fashion. These mechanisms are functional at a very early age in humans and spontaneously deployed in the wild by animals of different species. The recent years have witnessed terrific advances in unveiling the neural code(s) underlying numerosity representations and showing similarities as well as differences across species. In humans, during development, with the introduction of symbols for numbers and the implementation of the counting routines, the parietal system undergoes profound (yet still largely mysterious) modifications, such that the neural machinery previously evolved to represent approximate numerosity gets partially "recycled" to support the representation of exact number.

Color Vision, Cones, and Color-Coding in the Cortex

Conway, B. R. — Tue, 12 May 2009 18:01:39 PDT

Color processing begins with the absorption of light by cone photoreceptors, and progresses through a series of hierarchical stages: Retinal signals carrying color information are transmitted through the lateral geniculate nucleus of the thalamus (LGN) up to the primary visual cortex (V1). From V1, the signals are processed by the second visual area (V2); then by cells located in subcompartments ("globs") within the posterior inferior temporal (PIT) cortex, a brain region that encompasses area V4 and brain regions immediately anterior to V4. Color signals are then processed by regions deep within the inferior temporal (IT) cortex including area TE. As a heuristic, one can consider each of these stages to be involved in constructing a distinct aspect of the color percept. The three cone types are the basis for trichromacy; retinal ganglion cells that respond in an opponent fashion to activation of different cone classes are the basis for color opponency (these "cone-opponent" cells increase their firing rate above baseline to activation of one cone class and decrease their firing rate below baseline to activation of a different cone class); double-opponent neurons in the V1 generate local color contrast and are the building blocks for color constancy; glob cells elaborate the perception of hue; and IT integrates color perception in the context of behavior. Finally, though nothing is known, these signals presumably interface with motor programs and emotional centers of the brain to mediate the widely acknowledged emotional salience of color.

Cortical Changes Following Spinal Cord Injury with Emphasis on the Nogo Signaling System

Endo, T., Tominaga, T., Olson, L. — Tue, 12 May 2009 18:01:39 PDT

After spinal cord injury, structural as well as functional modifications occur in the adult CNS. Sites of plastic changes include the injured spinal cord itself as well as cortical and subcortical structures. Previously, cortical reorganization in response to sensory deprivation has mainly been studied using peripheral nerve injury models, and has led to a degree of understanding of mechanisms underlying reorganization and plastic changes. Deprivation or damage-induced CNS plasticity is not always beneficial for patients, and may underlie the development of conditions such as neuropathic pain and phantom sensations. Therefore, efforts not only to enhance, but also to control the capacity of plastic changes in the CNS, are of clinical relevance. Novel methods to stimulate plasticity as well as to monitor it, such as transcranial magnetic stimulation and functional magnetic resonance imaging, respectively, may be useful in diverse clinical situations such as spinal cord injury and stroke. Here, human and animal studies of spinal cord injury are reviewed, with special emphasis on the contribution of the Nogo signaling system to cortical plasticity.

The Neuroscientist Comments

Mon, 23 Mar 2009 10:17:05 PDT

Perspectives on Neuroscience and Behavior

Mon, 23 Mar 2009 10:17:05 PDT

Ischemic Injury to White Matter: An Age-Dependent Process

Baltan, S. — Mon, 23 Mar 2009 10:17:05 PDT

The risk for ischemic stroke increases drastically with age, although reasons for this remain unexplored. White matter (WM) and gray matter constitute equal proportions of the brain, and WM is injured in most strokes. Axonal injury and dysfunction are responsible for much of the disability associated with clinical deficits observed after stroke. The authors recently reported that central nervous system WM is inherently more vulnerable to ischemic injury in older mice, and the mechanisms of WM injury change as a function of age. Ischemic WM injury in older mice is predominately mediated by a Ca²⁺-independent excitotoxicity involving overactivation of AMPA/kainate receptors. Glutamate release, due to reverse glutamate transport, occurs earlier and is more robust in older mice that show up-regulation of GLT1, the main glutamate transporter. Blockade of NMDA receptors does not improve WM function after ischemia in the young but aggravates ischemic injury in older mice. The main goals of this research update are to summarize the evidence for equivalent brain insults inducing more damage with aging, and to highlight the importance of age in any successful stroke therapy.

Reviews: Mechanisms Mediating Brain Plasticity: IGF1 and Adult Hippocampal Neurogenesis

LLorens-Martin, M., Torres-Aleman, I., Trejo, J. L. — Mon, 23 Mar 2009 10:17:05 PDT

This review addresses the role of serum insulin-like growth factor 1 (IGF1) as one mechanism of adult neural plasticity, specifically, its regulation of hippocampal neurogenesis among other plasticity-related processes. It is suggested that IGF has been reused advantageously both for the control of energy expenditure as a function of the organism's activity and to protect, repair, and plastically modulate the brain. Moreover, because as the main source of IGF1 in the adult organism is outside the brain and its presence in this organ is a function of the activity, IGF1 becomes an ideal factor to induce plastic/neuroprotective functions as a function of the organism's activity. The link for this point of view comes from the original function of IGF1 during ontogeny/phylogeny, the promotion of cell survival and control of neural cell numbers, whereas one of the IGF1 functions in the adult brain is the control of hippocampal neurogenesis. The investigation of the IGF1 role as mediator of exercise effects suggests that many but not all the effects of physical activity are mediated by IGF1. These investigations have contributed to delimit the role of IGF1 as mediator of exercise actions, but at the same time are unveiling new roles for serum IGF1 inside the brain.

Synaptic Plasticity, Neurogenesis, and Functional Recovery after Spinal Cord Injury

Darian-Smith, C. — Mon, 23 Mar 2009 10:17:05 PDT

Spinal cord injury research has greatly expanded in recent years, but our understanding of the mechanisms that underlie the functional recovery that can occur over the weeks and months following the initial injury, is far from complete. To grasp the scope of the problem, it is important to begin by defining the sensorimotor pathways that might be involved by a spinal injury. This is done in the rodent and nonhuman primate, which are two of the most commonly used animal models in basic and translational spinal injury research. Many of the better known experimentally induced models are then reviewed in terms of the pathways they involve and the reorganization and recovery that have been shown to follow. The better understood neuronal mechanisms mediating such post-injury plasticity, including dendritic spine growth and axonal sprouting, are then examined.

Individual Differences in Episodic Memory: The Role of Self-initiated Encoding Strategies

Kirchhoff, B. A. — Mon, 23 Mar 2009 10:17:05 PDT

Individuals' abilities to form and retrieve episodic memories vary widely. Consistent with this, there are substantial individual differences in brain activity during encoding and retrieval that are associated with individual differences in memory performance. Growing evidence suggests that individual differences in self-initiated encoding strategy use play an important role in individual differences in episodic memory and brain activity during intentional encoding. This review examines the role of individual differences in self-initiated encoding strategy use in individual differences in episodic memory, and outlines the major findings of brain lesion and functional neuroimaging studies that characterize the neural correlates of individual differences in self-initiated encoding strategy use. The relevance of individual differences in self-initiated encoding strategy use to understanding episodic memory impairments and alterations in brain activity in clinical populations such as individuals with schizophrenia is also discussed.

Agrin, Aquaporin-4, and Astrocyte Polarity as an Important Feature of the Blood-Brain Barrier

Wolburg, H., Noell, S., Wolburg-Buchholz, K., Mack, A., Fallier-Becker, P. — Mon, 23 Mar 2009 10:17:05 PDT

The blood-brain barrier (BBB) does not exclusively refer to brain endothelial cells, which are the site of the barrier proper. In the past few years, it has become increasingly clear that BBB endothelial cells depend considerably on the brain microenvironment to a degree exceeding the environmental influence in other organs. The concept of the BBB has been continuously developed over the decades, culminating now in the recognition that endothelial cell function in the brain is not limited to simply mediating energy and oxygen transfer between blood and neural tissue. Endothelial cells are rather "Janus-headed beings" that are active partners of both luminal molecules and cells, as well as subendothelial cells such as pericytes, astrocytes, and neurons. In this overview, the authors present and discuss both the role of astroglial cells in managing the BBB and aspects of pathological alterations in the brain as far as the BBB is involved. After a brief introduction of the BBB that describes the structure and function of the brain capillary endothelial cells, the authors report on both the water channel protein aquaporin-4 (AQP4) in astrocytes and the extracellular matrix between astrocytes/pericytes and endothelial cells. The AQP4 has an important impact on the homeostasis in the brain parenchyma; however, the mechanistic cascade from the composition of the astrocyte membrane to the maintenance of BBB properties in the endothelial cells, including their tight junction formation, is still completely unknown.

Respiratory Circuits: Function, Mechanisms, Topology, and Pathology

Mironov, S. — Mon, 23 Mar 2009 10:17:05 PDT

Neuroscientists have long sought to understand how circuits in the nervous system are organized to generate the precise neural outputs that underlie particular behaviors. Recent studies deepened our understanding of the mechanisms responsible for the generation of the rhythmic output for breathing. Here, the author focuses on issues that are pertinent for the respiratory network and considers its organization and how it derives the functional output. The author discusses pacemaker and network mechanisms of rhythm generation, which are now combined into a novel concept of emergent network activity due to coherent excitation of pacemaker groups. He discusses subcellular basis of this hypothesis and possible mechanisms of synchronization within respiratory network. These new findings in respiratory neuroscience are further applied to explain modifications in breathing during hypoxia and possible origins of respiratory disorders that may be acquired during neural development and aging.