Showing papers in "Nature Reviews Neuroscience in 2006"
TL;DR: Specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood–brain barrier function are explored to lead to the development of new protective and restorative therapies.
Abstract: The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
4,578 citations
TL;DR: This work reviews the emerging literature that relates social cognition to the medial frontal cortex and proposes a theoretical model of medial frontal cortical function relevant to different aspects of social cognitive processing.
Abstract: Social interaction is a cornerstone of human life, yet the neural mechanisms underlying social cognition are poorly understood. Recently, research that integrates approaches from neuroscience and social psychology has begun to shed light on these processes, and converging evidence from neuroimaging studies suggests a unique role for the medial frontal cortex. We review the emerging literature that relates social cognition to the medial frontal cortex and, on the basis of anatomical and functional characteristics of this brain region, propose a theoretical model of medial frontal cortical function relevant to different aspects of social cognitive processing.
3,426 citations
TL;DR: Recent work combining modern behavioural assays and neurobiological analysis of the basal ganglia has begun to yield insights into the neural basis of habit formation.
Abstract: Many organisms, especially humans, are characterized by their capacity for intentional, goal-directed actions. However, similar behaviours often proceed automatically, as habitual responses to antecedent stimuli. How are goal-directed actions transformed into habitual responses? Recent work combining modern behavioural assays and neurobiological analysis of the basal ganglia has begun to yield insights into the neural basis of habit formation.
2,133 citations
TL;DR: Theoretical studies suggest that the medial entorhinal cortex might perform some of the essential underlying computations by means of a unique, periodic synaptic matrix that could be self-organized in early development through a simple, symmetry-breaking operation.
Abstract: The hippocampal formation can encode relative spatial location, without reference to external cues, by the integration of linear and angular self-motion (path integration). Theoretical studies, in conjunction with recent empirical discoveries, suggest that the medial entorhinal cortex (MEC) might perform some of the essential underlying computations by means of a unique, periodic synaptic matrix that could be self-organized in early development through a simple, symmetry-breaking operation. The scale at which space is represented increases systematically along the dorsoventral axis in both the hippocampus and the MEC, apparently because of systematic variation in the gain of a movement-speed signal. Convergence of spatially periodic input at multiple scales, from so-called grid cells in the entorhinal cortex, might result in non-periodic spatial firing patterns (place fields) in the hippocampus.
1,747 citations
TL;DR: This work has shown that it is possible to accurately decode a person's conscious experience based only on non-invasive measurements of their brain activity, and can also be extended to other types of mental state, such as covert attitudes and lie detection.
Abstract: Recent advances in human neuroimaging have shown that it is possible to accurately decode a person's conscious experience based only on non-invasive measurements of their brain activity. Such 'brain reading' has mostly been studied in the domain of visual perception, where it helps reveal the way in which individual experiences are encoded in the human brain. The same approach can also be extended to other types of mental state, such as covert attitudes and lie detection. Such applications raise important ethical issues concerning the privacy of personal thought.
1,714 citations
TL;DR: This work reviews studies that address the interaction between neuronal noise and population codes, and discusses their implications for population coding in general.
Abstract: How the brain encodes information in population activity, and how it combines and manipulates that activity as it carries out computations, are questions that lie at the heart of systems neuroscience. During the past decade, with the advent of multi-electrode recording and improved theoretical models, these questions have begun to yield answers. However, a complete understanding of neuronal variability, and, in particular, how it affects population codes, is missing. This is because variability in the brain is typically correlated, and although the exact effects of these correlations are not known, it is known that they can be large. Here, we review studies that address the interaction between neuronal noise and population codes, and discuss their implications for population coding in general.
1,649 citations
TL;DR: This review examines how the sympathetic tone to cardiovascular organs is generated, and discusses how elevated sympathetic tone can contribute to hypertension.
Abstract: The sympathetic nervous system is an important regulator of blood pressure Guyenet describes the central control regions that influence the activity of sympathetic efferent neurons and their potential contribution to neurogenic hypertension Hypertension — the chronic elevation of blood pressure — is a major human health problem In most cases, the root cause of the disease remains unknown, but there is mounting evidence that many forms of hypertension are initiated and maintained by an elevated sympathetic tone This review examines how the sympathetic tone to cardiovascular organs is generated, and discusses how elevated sympathetic tone can contribute to hypertension
1,625 citations
TL;DR: Cognitive neuroscientists have begun to elucidate the psychological and neural mechanisms underlying emotional retention advantages in the human brain, revealing new insights into the reactivation of latent emotional associations and the recollection of personal episodes from the remote past.
Abstract: LaBar and Cabeza review the powerful effects of emotion on memory. These influences are mediated by the amygdala and its interactions with medial temporal and prefrontal regions, and affect memory from the encoding and consolidation stages through to long-term retrieval.
1,552 citations
TL;DR: Findings on the environmental modulators of pathogenesis and gene–environment interactions in CNS disorders, and their therapeutic implications, are reviewed.
Abstract: Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions Here, we review these findings on the environmental modulators of pathogenesis and gene-environment interactions in CNS disorders, and discuss their therapeutic implications
1,546 citations
TL;DR: The molecular basis of inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring are evaluated and their contributions to the limitation of long-distance axon repair and other types of structural plasticity are evaluated.
Abstract: Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of long-distance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.
1,429 citations
TL;DR: A recent review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies as discussed by the authors.
Abstract: All antidepressants in use today act via the monoamine neurotransmitters However, only ∼50% of individuals with depression show full remission Berton and Nestler review recent development of alternative, non-monoamine-based antidepressants, highlighting the obstacles and some of the most promising strategies All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters This is unfortunate, because only ∼50% of individuals with depression show full remission in response to these mechanisms This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies
TL;DR: The striking quantity and diversity of sex-related influences on brain function indicate that the still widespread assumption that sex influences are negligible cannot be justified, and probably retards progress in the field.
Abstract: A rapidly burgeoning literature documents copious sex influences on brain anatomy, chemistry and function. This article highlights some of the more intriguing recent discoveries and their implications. Consideration of the effects of sex can help to explain seemingly contradictory findings. Research into sex influences is mandatory to fully understand a host of brain disorders with sex differences in their incidence and/or nature. The striking quantity and diversity of sex-related influences on brain function indicate that the still widespread assumption that sex influences are negligible cannot be justified, and probably retards progress in our field.
TL;DR: This work has shown that in two areas of the adult brain, new neurons are generated throughout life and form an integral part of the normal functional circuitry, revealing a plastic mechanism by which the brain's performance can be optimized for a given environment.
Abstract: The adult brain is a plastic place. To ensure that the mature nervous system's control of behaviour is flexible in the face of a varying environment, morphological and physiological changes are possible at many levels, including that of the entire cell. In two areas of the adult brain - the olfactory bulb and the dentate gyrus - new neurons are generated throughout life and form an integral part of the normal functional circuitry. This process is not fixed, but highly modulated, revealing a plastic mechanism by which the brain's performance can be optimized for a given environment. The functional benefits of this whole-cell plasticity, however, remain a matter for debate.
TL;DR: Major advances in understanding of age-related changes in the medial temporal lobe and prefrontal cortex are discussed and how these changes in functional plasticity contribute to behavioural impairments in the absence of significant pathology.
Abstract: The mechanisms involved in plasticity in the nervous system are thought to support cognition, and some of these processes are affected during normal ageing. Notably, cognitive functions that rely on the medial temporal lobe and prefrontal cortex, such as learning, memory and executive function, show considerable age-related decline. It is therefore not surprising that several neural mechanisms in these brain areas also seem to be particularly vulnerable during the ageing process. In this review, we discuss major advances in our understanding of age-related changes in the medial temporal lobe and prefrontal cortex and how these changes in functional plasticity contribute to behavioural impairments in the absence of significant pathology.
TL;DR: The neurophysiology of the mirror neuron system and its role in social cognition is reviewed and the clinical implications of mirror neuron dysfunction are discussed.
Abstract: The discovery of premotor and parietal cells known as mirror neurons in the macaque brain that fire not only when the animal is in action, but also when it observes others carrying out the same actions provides a plausible neurophysiological mechanism for a variety of important social behaviours, from imitation to empathy. Recent data also show that dysfunction of the mirror neuron system in humans might be a core deficit in autism, a socially isolating condition. Here, we review the neurophysiology of the mirror neuron system and its role in social cognition and discuss the clinical implications of mirror neuron dysfunction.
TL;DR: Opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene–environment interactions in psychiatry are discussed.
Abstract: Gene-environment interaction research in psychiatry is new, and is a natural ally of neuroscience. Mental disorders have known environmental causes, but there is heterogeneity in the response to each causal factor, which gene-environment findings attribute to genetic differences at the DNA sequence level. Such findings come from epidemiology, an ideal branch of science for showing that a gene-environment interactions exist in nature and affect a significant fraction of disease cases. The complementary discipline of epidemiology, experimental neuroscience, fuels gene-environment hypotheses and investigates underlying neural mechanisms. This article discusses opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene-environment interactions.
TL;DR: It is argued that the time is right to begin assimilating the wealth of data that has been accumulated over the past century and start building biologically accurate models of the brain from first principles to aid the understanding of brain function and dysfunction.
Abstract: Markram describes the impressive aims of the Blue Brain Project, in which the enormous computing power of IBM's Blue Gene supercomputer is being harnessed to build biologically accurate models of the neocortical column and, ultimately, the whole brain.
TL;DR: This work evaluates claims and some counter-claims made about the physiological importance of these enzymes and the potential of their inhibitors in the light of what the authors know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitor.
Abstract: Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.
TL;DR: Recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion are illustrated.
Abstract: Using schizophrenia as an example, Meyer-Lindenberg and Weinberger review the effectiveness of the intermediate phenotype concept for characterizing the neural systems affected by risk gene variants, with a view to elucidating mechanistic aspects of brain function implicated in psychiatric disease. Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.
TL;DR: Examples from theoretical and experimental studies of invertebrates and vertebrates are used to explore several issues relevant to understanding the precision of tuning of synaptic and intrinsic currents for the operation of functional neuronal circuits.
Abstract: Neurons in most animals live a very long time relative to the half-lives of all of the proteins that govern excitability and synaptic transmission. Consequently, homeostatic mechanisms are necessary to ensure stable neuronal and network function over an animal's lifetime. To understand how these homeostatic mechanisms might function, it is crucial to understand how tightly regulated synaptic and intrinsic properties must be for adequate network performance, and the extent to which compensatory mechanisms allow for multiple solutions to the production of similar behaviour. Here, we use examples from theoretical and experimental studies of invertebrates and vertebrates to explore several issues relevant to understanding the precision of tuning of synaptic and intrinsic currents for the operation of functional neuronal circuits.
TL;DR: An overview of the mechanisms for motor neuron death and the role of non-neuronal cells in ALS is presented and new insights are generated into the diverse molecular pathways involved in ALS pathogenesis.
Abstract: Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.
TL;DR: It is predicted that combinations of strategies will lead to improvements in outcome after SCI, and that individual therapies are unlikely to provide a panacea.
Abstract: Spinal cord injury (SCI) can lead to paraplegia or quadriplegia. Although there are no fully restorative treatments for SCI, various rehabilitative, cellular and molecular therapies have been tested in animal models. Many of these have reached, or are approaching, clinical trials. Here, we review these potential therapies, with an emphasis on the need for reproducible evidence of safety and efficacy. Individual therapies are unlikely to provide a panacea. Rather, we predict that combinations of strategies will lead to improvements in outcome after SCI. Basic scientific research should provide a rational basis for tailoring specific combinations of clinical therapies to different types of SCI.
TL;DR: Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.
Abstract: Everyone ages, but only some will develop a neurodegenerative disorder in the process. Disease might occur when cells fail to respond adaptively to age-related increases in oxidative, metabolic and ionic stress, thereby resulting in the accumulation of damaged proteins, DNA and membranes. Determinants of neuronal vulnerability might include cell size and location, metabolism of disease-specific proteins and a repertoire of signal transduction pathways and stress resistance mechanisms. Emerging evidence on protein interaction networks that monitor and respond to the normal ageing process suggests that successful neural ageing is possible for most people, but also cautions that cures for neurodegenerative disorders are unlikely in the near future.
TL;DR: Current research concentrates on the identification of common targets for future analgesic and antipruritic therapy, and there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors.
Abstract: Itch and pain are distinct sensations processed by different but overlapping neural pathways. Ikomaet al. review recent evidence on the molecular mechanisms that underlie itch sensation, highlighting the complex interaction with pain processing, and discuss the therapeutic implications. The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.
TL;DR: Recent data that are beginning to illuminate the origins and specification of distinct subgroups of cortical interneurons are discussed.
Abstract: GABA-containing interneurons are crucial to both the development and function of the cerebral cortex. Unlike cortical projection neurons, which have a relatively conserved set of characteristics, interneurons include multiple phenotypes that vary on morphological, physiological and neurochemical axes. This diversity, and the relatively late, context-dependent maturation of defining features, has challenged efforts to uncover the transcriptional control of cortical interneuron development. Here, we discuss recent data that are beginning to illuminate the origins and specification of distinct subgroups of cortical interneurons.
TL;DR: The relatively well-developed models of how the cerebellum processes information from the motor cortex might be extended to explain how it could also process information from an area of origin in the cerebral cortex.
Abstract: Evidence has been accumulating that the primate cerebellum contributes not only to motor control, but also to higher 'cognitive' function. However, there is no consensus about how the cerebellum processes such information. The answer to this puzzle can be found in the nature of cerebellar connections to areas of the cerebral cortex (particularly the prefrontal cortex) and in the uniformity of its intrinsic cellular organization, which implies uniformity in information processing regardless of the area of origin in the cerebral cortex. With this in mind, the relatively well-developed models of how the cerebellum processes information from the motor cortex might be extended to explain how it could also process information from the prefrontal cortex.
TL;DR: How DJ1, PINK1 and OMI/HTRA2 fit into and enhance the understanding of the role of mitochondrial dysfunction in Parkinson's disease are reviewed, and how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease is considered.
Abstract: The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.
TL;DR: The recently demonstrated ability of neuropeptides to prime vesicle stores for activity-dependent release could lead to a temporary functional reorganization of neuronal networks harbouring specific peptide receptors, providing a substrate for long-lasting effects.
Abstract: Neuropeptides that are released from dendrites, such as oxytocin and vasopressin, function as autocrine or paracrine signals at their site of origin, but can also act at distant brain targets to evoke long-lasting changes in behaviour. Oxytocin, for instance, has profound effects on social bonding that are exerted at sites that richly express oxytocin receptors, but which are innervated by few, if any, oxytocin-containing projections. How can a prolonged, diffuse signal have coherent behavioural consequences? The recently demonstrated ability of neuropeptides to prime vesicle stores for activity-dependent release could lead to a temporary functional reorganization of neuronal networks harbouring specific peptide receptors, providing a substrate for long-lasting effects.
TL;DR: Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells.
Abstract: Signals through the Notch receptors are used throughout development to control cellular fate choices Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells As we review here, Notch signalling affects the development of the nervous system at many different levels Understanding the complex genetic circuitry that allows Notch signals to affect specific cell fates in a context-specific manner defines the next challenge, especially as such an understanding might have important implications for regenerative medicine
TL;DR: The involvement of ATP and adenosine receptors in neuron–glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance are reviewed.
Abstract: Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron-glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.