Showing papers in "Nature Reviews Neuroscience in 2012"
TL;DR: High-density recordings of field activity in animals and subdural grid recordings in humans can provide insight into the cooperative behaviour of neurons, their average synaptic input and their spiking output, and can increase the understanding of how these processes contribute to the extracellular signal.
Abstract: Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular signal is the synaptic transmembrane current, other sources — including Na+ and Ca2+ spikes, ionic fluxes through voltage- and ligand-gated channels, and intrinsic membrane oscillations — can substantially shape the extracellular field. High-density recordings of field activity in animals and subdural grid recordings in humans, combined with recently developed data processing tools and computational modelling, can provide insight into the cooperative behaviour of neurons, their average synaptic input and their spiking output, and can increase our understanding of how these processes contribute to the extracellular signal.
3,366 citations
TL;DR: The emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
Abstract: Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS — possibly through neural, endocrine and immune pathways — and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
3,058 citations
TL;DR: It is proposed that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations.
Abstract: On the basis of data from brain network science, Bullmore and Sporns propose that brain organization is shaped by an economical trade-off between minimizing wiring cost and maximizing the efficiency of information transfer between neuronal populations and discuss this idea in the context of psychiatric and neurological disorders. The brain is expensive, incurring high material and metabolic costs for its size — relative to the size of the body — and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a 'rich club' of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development.
2,646 citations
TL;DR: Normalization was developed to explain responses in the primary visual cortex and is now thought to operate throughout the visual system, and in many other sensory modalities and brain regions, suggesting that it serves as a canonical neural computation.
Abstract: There is increasing evidence that the brain relies on a set of canonical neural computations, repeating them across brain regions and modalities to apply similar operations to different problems. A promising candidate for such a computation is normalization, in which the responses of neurons are divided by a common factor that typically includes the summed activity of a pool of neurons. Normalization was developed to explain responses in the primary visual cortex and is now thought to operate throughout the visual system, and in many other sensory modalities and brain regions. Normalization may underlie operations such as the representation of odours, the modulatory effects of visual attention, the encoding of value and the integration of multisensory information. Its presence in such a diversity of neural systems in multiple species, from invertebrates to mammals, suggests that it serves as a canonical neural computation.
1,619 citations
TL;DR: Developmental neuroimaging studies do not support a simple model of frontal cortical immaturity, and growing evidence points to the importance of changes in social and affective processing, which begin around the onset of puberty, as crucial to understanding these adolescent vulnerabilities.
Abstract: Research has demonstrated that extensive structural and functional brain development continues throughout adolescence. A popular notion emerging from this work states that a relative immaturity in frontal cortical neural systems could explain adolescents' high rates of risk-taking, substance use and other dangerous behaviours. However, developmental neuroimaging studies do not support a simple model of frontal cortical immaturity. Rather, growing evidence points to the importance of changes in social and affective processing, which begin around the onset of puberty, as crucial to understanding these adolescent vulnerabilities. These changes in social-affective processing also may confer some adaptive advantages, such as greater flexibility in adjusting one's intrinsic motivations and goal priorities amidst changing social contexts in adolescence.
1,567 citations
TL;DR: This Review attempts to present the current state of understanding of post-traumatic stress disorder on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.
Abstract: Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.
1,177 citations
TL;DR: It is proposed that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.
Abstract: Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the interactions between brain regions during cognitive processes by assessing correlations between neuronal oscillations in different regions of the primate cerebral cortex. These studies have opened a new window onto the large-scale circuit mechanisms underlying sensorimotor decision-making and top-down attention. We propose that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.
1,149 citations
TL;DR: Understanding of the mechanisms by which stress and glucocorticoids affect glutamate transmission provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
Abstract: Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
1,121 citations
TL;DR: With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions on the basis of the kynurenine pathway.
Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
1,097 citations
TL;DR: Current trends and unresolved issues in the cognitive neuroscience of ageing are discussed and it is less clear how age differences in brain activity relate to cognitive performance.
Abstract: The availability of neuroimaging technology has spurred a marked increase in the human cognitive neuroscience literature, including the study of cognitive ageing. Although there is a growing consensus that the ageing brain retains considerable plasticity of function, currently measured primarily by means of functional MRI, it is less clear how age differences in brain activity relate to cognitive performance. The field is also hampered by the complexity of the ageing process itself and the large number of factors that are influenced by age. In this Review, current trends and unresolved issues in the cognitive neuroscience of ageing are discussed.
1,032 citations
TL;DR: It is suggested that the PRC and PHC–RSC are core components of two separate large-scale cortical networks that are dissociable by neuroanatomy, susceptibility to disease and function.
Abstract: Although the perirhinal cortex (PRC), parahippocampal cortex (PHC) and retrosplenial cortex (RSC) have an essential role in memory, the precise functions of these areas are poorly understood. Here, we review the anatomical and functional characteristics of these areas based on studies in humans, monkeys and rats. Our Review suggests that the PRC and PHC-RSC are core components of two separate large-scale cortical networks that are dissociable by neuroanatomy, susceptibility to disease and function. These networks not only support different types of memory but also appear to support different aspects of cognition.
TL;DR: In conclusion, animal models demonstrate that the molecular basis of disruption is linked to specific defects in the development and function of interneurons — the cells that are responsible for establishing inhibitory circuits in the brain.
Abstract: The notion that the disruption of inhibitory circuits might underlie certain clinical features — notably cognitive impairment — in various neuropsychiatric disorders, including schizophrenia and autism, is receiving considerable attention. Focusing heavily on studies in animal models, Oscar Marin reviews the evidence indicating that the basis of such disruption is linked to specific defects in interneuron development and function.
TL;DR: In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse, and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors.
Abstract: Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.
TL;DR: Findings from studies in which subjects receive ambiguous multisensory information about the location and appearance of their own body may form the basis for a neurobiological model of bodily self-consciousness.
Abstract: Recent research has linked bodily self-consciousness to the processing and integration of multisensory bodily signals in temporoparietal, premotor, posterior parietal and extrastriate cortices. Studies in which subjects receive ambiguous multisensory information about the location and appearance of their own body have shown that these brain areas reflect the conscious experience of identifying with the body (self-identification (also known as body-ownership)), the experience of where 'I' am in space (self-location) and the experience of the position from where 'I' perceive the world (first-person perspective). Along with phenomena of altered states of self-consciousness in neurological patients and electrophysiological data from non-human primates, these findings may form the basis for a neurobiological model of bodily self-consciousness.
TL;DR: The multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation.
Abstract: Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis - they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation.
TL;DR: A survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming.
Abstract: A clear majority of patients with chronic pain are women; however, it has been surprisingly difficult to determine whether this sex bias corresponds to actual sex differences in pain sensitivity. A survey of the currently available epidemiological and laboratory data indicates that the evidence for clinical and experimental sex differences in pain is overwhelming. Various explanations for this phenomenon have been given, ranging from experiential and sociocultural differences in pain experience between men and women to hormonally and genetically driven sex differences in brain neurochemistry.
TL;DR: Studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals are reviewed.
Abstract: Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.
TL;DR: Research into the mechanisms that regulate mitochondrial transport is an important emerging frontier into the pathogenesis of several major neurological disorders.
Abstract: Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier.
TL;DR: The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models.
Abstract: Optogenetic tools have provided a new way to establish causal relationships between brain activity and behaviour in health and disease. Although no animal model captures human disease precisely, behaviours that recapitulate disease symptoms may be elicited and modulated by optogenetic methods, including behaviours that are relevant to anxiety, fear, depression, addiction, autism and parkinsonism. The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models.
TL;DR: Emerging evidence suggests that experiences of social pain — the painful feelings associated with social disconnection — rely on some of the same neurobiological substrates that underlie experiences of physical pain.
Abstract: Experiences of social rejection, exclusion or loss are generally considered to be some of the most 'painful' experiences that we endure. Indeed, many of us go to great lengths to avoid situations that may engender these experiences (such as public speaking). Why is it that these negative social experiences have such a profound effect on our emotional well-being? Emerging evidence suggests that experiences of social pain — the painful feelings associated with social disconnection — rely on some of the same neurobiological substrates that underlie experiences of physical pain. Understanding the ways in which physical and social pain overlap may provide new insights into the surprising relationship between these two types of experiences.
TL;DR: The goal of this article is to integrate psycholinguistic and motor control approaches to speech production into a neuroanatomically grounded, hierarchical state feedback control model of speech production.
Abstract: The study of speech production has largely been divided into investigations of lower-level articulatory motor control and of higher-level linguistic processing, with these research traditions rarely interacting. In this Opinion article, Hickok argues that these approaches have much to offer each other, and he presents a model of speech production that incorporates ideas from both research traditions and findings from neuroscientific studies of sensorimotor integration. Speech production has been studied predominantly from within two traditions, psycholinguistics and motor control. These traditions have rarely interacted, and the resulting chasm between these approaches seems to reflect a level of analysis difference: whereas motor control is concerned with lower-level articulatory control, psycholinguistics focuses on higher-level linguistic processing. However, closer examination of both approaches reveals a substantial convergence of ideas. The goal of this article is to integrate psycholinguistic and motor control approaches to speech production. The result of this synthesis is a neuroanatomically grounded, hierarchical state feedback control model of speech production.
TL;DR: Experimental studies are attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein, and the distinct possibility of pleotropic or combined effects.
Abstract: RNA-binding proteins, and in particular TAR DNA-binding protein 43 (TDP43), are central to the pathogenesis of motor neuron diseases and related neurodegenerative disorders. Studies on human tissue have implicated several possible mechanisms of disease and experimental studies are now attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein. In addition, the distinct possibility of pleotropic or combined effects - in which gains of toxic properties and losses of normal TDP43 functions act together - needs to be considered.
TL;DR: This expanding inventory of small and long non-coding RNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis.
Abstract: Novel classes of small and long non-coding RNAs (ncRNAs) are being characterized at a rapid pace, driven by recent paradigm shifts in our understanding of genomic architecture, regulation and transcriptional output, as well as by innovations in sequencing technologies and computational and systems biology. These ncRNAs can interact with DNA, RNA and protein molecules; engage in diverse structural, functional and regulatory activities; and have roles in nuclear organization and transcriptional, post-transcriptional and epigenetic processes. This expanding inventory of ncRNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis.
TL;DR: Data show that fear of painful stimuli, predators and aggressive members of the same species are processed in independent neural circuits that involve the amygdala and downstream hypothalamic and brainstem circuits.
Abstract: Fear is an emotion that has powerful effects on behaviour and physiology across animal species. It is accepted that the amygdala has a central role in processing fear. However, it is less widely appreciated that distinct amygdala outputs and downstream circuits are involved in different types of fear. Data show that fear of painful stimuli, predators and aggressive members of the same species are processed in independent neural circuits that involve the amygdala and downstream hypothalamic and brainstem circuits. Here, we discuss data supporting multiple fear pathways and the implications of this distributed system for understanding and treating fear.
TL;DR: It is likely that no single factor can explain the neuroprotection provided by hypothermia, but understanding its myriad effects may shed light on important neuroprotective mechanisms.
Abstract: Cooling can reduce primary injury and prevent secondary injury to the brain after insults in certain clinical settings and in animal models of brain insult. The mechanisms that underlie the protective effects of cooling - also known as therapeutic hypothermia - are slowly beginning to be understood. Hypothermia influences multiple aspects of brain physiology in the acute, subacute and chronic stages of ischaemia. It affects pathways leading to excitotoxicity, apoptosis, inflammation and free radical production, as well as blood flow, metabolism and blood-brain barrier integrity. Hypothermia may also influence neurogenesis, gliogenesis and angiogenesis after injury. It is likely that no single factor can explain the neuroprotection provided by hypothermia, but understanding its myriad effects may shed light on important neuroprotective mechanisms.
TL;DR: It is proposed that the different forms of plasticity in the granular layer and the molecular layer operate synergistically in a temporally and spatially distributed manner, so as to ultimately create optimal output for behaviour.
Abstract: Studies on synaptic plasticity in the context of learning have been dominated by the view that a single, particular type of plasticity forms the underlying mechanism for a particular type of learning. However, emerging evidence shows that many forms of synaptic and intrinsic plasticity at different sites are induced conjunctively during procedural memory formation in the cerebellum. Here, we review the main forms of long-term plasticity in the cerebellar cortex that underlie motor learning. We propose that the different forms of plasticity in the granular layer and the molecular layer operate synergistically in a temporally and spatially distributed manner, so as to ultimately create optimal output for behaviour.
TL;DR: The current evidence for the link between addiction and obesity is examined, identifying several fundamental shortcomings in the model, as well as weaknesses and inconsistencies in the empirical support for it from human neuroscientific research.
Abstract: An increasingly influential perspective conceptualizes both obesity and overeating as a food addiction accompanied by corresponding brain changes. Because there are far-reaching implications for clinical practice and social policy if it becomes widely accepted, a critical evaluation of this model is important. We examine the current evidence for the link between addiction and obesity, identifying several fundamental shortcomings in the model, as well as weaknesses and inconsistencies in the empirical support for it from human neuroscientific research.
TL;DR: Molecular analysis suggests that in some fast central synapses, transmitter release is triggered by a small number of Ca2+ channels that are coupled toCa2+ sensors at the nanometre scale.
Abstract: The physical distance between presynaptic Ca2+ channels and the Ca2+ sensors that trigger exocytosis of neurotransmitter-containing vesicles is a key determinant of the signalling properties of synapses in the nervous system. Recent functional analysis indicates that in some fast central synapses, transmitter release is triggered by a small number of Ca2+ channels that are coupled to Ca2+ sensors at the nanometre scale. Molecular analysis suggests that this tight coupling is generated by protein–protein interactions involving Ca2+ channels, Ca2+ sensors and various other synaptic proteins. Nanodomain coupling has several functional advantages, as it increases the efficacy, speed and energy efficiency of synaptic transmission.
TL;DR: It is argued that MS may be an 'immunological convolution' between an underlying primary degenerative disorder and the host's aberrant immune response, with non-inflammatory primary progressive MS as the 'real' MS, with inflammatory forms reflecting secondary, albeit very important, reactions.
Abstract: Multiple sclerosis (MS) is generally considered to be an autoimmune, inflammatory disease. In this provocative Perspective, Stys and colleagues propose that non-inflammatory, primary progressive MS is the 'real' MS, and that inflammatory forms of the disorder reflect an aberrant immune reaction to ongoing cytodegeneration.
TL;DR: Current knowledge on the roles and regulatory mechanisms of axonal mRNA translation are reviewed and emerging links to axon guidance, survival, regeneration and neurological disorders are discussed.
Abstract: Local mRNA translation provides an efficient mechanism by which highly polarized cells such as neurons can respond to extrinsic signals Holt and colleagues describe the growing evidence for the importance of local axonal mRNA translation and protein synthesis in various aspects of nervous system development and function