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  • Epithelial–Neuronal Communication in the Colon: Implications for Visceral Pain
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-23
    Sarah A. Najjar; Brian M. Davis; Kathryn M. Albers

    Visceral hypersensitivity and pain result, at least in part, from increased excitability of primary afferents that innervate the colon. In addition to intrinsic changes in these neurons, emerging evidence indicates that changes in lining epithelial cells may also contribute to increased excitability. Here we review recent studies on how colon epithelial cells communicate directly with colon afferents. Specifically, anatomical studies revealed specialized synaptic connections between epithelial cells and nerve fibers and studies using optogenetic activation of the epithelium showed initiation of pain-like responses. We review the possible mechanisms of epithelial–neuronal communication and provide an overview of the possible neurotransmitters and receptors involved. Understanding the biology of this interface and how it changes in pathological conditions may provide new treatments for visceral pain conditions.

  • Ion Channel Functions in Early Brain Development
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-17
    Richard S. Smith; Christopher A. Walsh

    During prenatal brain development, ion channels are ubiquitous across several cell types, including progenitor cells and migrating neurons but their function has not been clear. In the past, ion channel dysfunction has been primarily studied in the context of postnatal, differentiated neurons that fire action potentials – notably ion channels mutated in the epilepsies – yet data now support a surprising role in prenatal human brain disorders as well. Modern gene discovery approaches have identified defective ion channels in individuals with cerebral cortex malformations, which reflect abnormalities in early-to-middle stages of embryonic development (prior to ubiquitous action potentials). These human genetics studies and recent in utero animal modeling work suggest that precise control of ionic flux (calcium, sodium, and potassium) contributes to in utero developmental processes such as neural proliferation, migration, and differentiation.

  • A Hierarchy of Autonomous Systems for Vocal Production
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-16
    Yisi S. Zhang; Asif A. Ghazanfar

    Vocal production is hierarchical in the time domain. These hierarchies build upon biomechanical and neural dynamics across various timescales. We review studies in marmoset monkeys, songbirds, and other vertebrates. To organize these data in an accessible and across-species framework, we interpret the different timescales of vocal production as belonging to different levels of an autonomous systems hierarchy. The first level accounts for vocal acoustics produced on short timescales; subsequent levels account for longer timescales of vocal output. The hierarchy of autonomous systems that we put forth accounts for vocal patterning, sequence generation, dyadic interactions, and context dependence by sequentially incorporating central pattern generators, intrinsic drives, and sensory signals from the environment. We then show the framework’s utility by providing an integrative explanation of infant vocal production learning in which social feedback modulates infant vocal acoustics through the tuning of a drive signal.

  • Evolutionary Expansion of Human Cerebellar Germinal Zones
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-15
    Matthew G. Keefe; Tomasz J. Nowakowski

    Haldipur et al. explored the developmental origins of the human cerebellum, which has gained growing appreciation for its involvement in human cognition. The authors discovered human-unique expansion and maintenance of cerebellar germinal zones, reminiscent of processes in the developing human cerebral cortex necessary for generating expanded neuronal populations.

  • Diverse Mechanisms of Sound Frequency Discrimination in the Vertebrate Cochlea
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-15
    Robert Fettiplace

    Discrimination of different sound frequencies is pivotal to recognizing and localizing friend and foe. Here, I review the various hair cell-tuning mechanisms used among vertebrates. Electrical resonance, filtering of the receptor potential by voltage-dependent ion channels, is ubiquitous in all non-mammals, but has an upper limit of ~1 kHz. The frequency range is extended by mechanical resonance of the hair bundles in frogs and lizards, but may need active hair-bundle motion to achieve sharp tuning up to 5 kHz. Tuning in mammals uses somatic motility of outer hair cells, underpinned by the membrane protein prestin, to expand the frequency range. The bird cochlea may also use prestin at high frequencies, but hair cells <1 kHz show electrical resonance.

  • The Sigma-1 Receptor at the Crossroad of Proteostasis, Neurodegeneration, and Autophagy
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-06
    Maximilian G. Christ; Albrecht M. Clement; Christian Behl

    Neurodegenerative diseases are linked to dysfunctional proteostasis and disturbed autophagy. Here, we discuss how the sigma-1 receptor (Sig-1R) may act at the intersection of this interaction, as loss-of-function mutations of this unique chaperone are associated with defective autophagy and its pharmacological activation induces autophagic activity.

  • Is Ca2+ Essential for Synaptic Vesicle Endocytosis?
    Trends Neurosci. (IF 12.314) Pub Date : 2020-01-03
    Natali L. Chanaday; Ege T. Kavalali

    Synaptic vesicle fusion is coupled to swift retrieval of vesicle components from the synaptic plasma membrane. Ca2+ has been assumed to be a key mediator of this coupling. In a recent study, Orlando et al. unequivocally demonstrate that Ca2+ is not essential for synaptic vesicle retrieval.

  • Zona Incerta: An Integrative Node for Global Behavioral Modulation
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-18
    Xiyue Wang; Xiao-lin Chou; Li I. Zhang; Huizhong Whit Tao

    Zona incerta (ZI) is a largely inhibitory subthalamic region connecting with many brain areas. Early studies have suggested involvement of ZI in various functions such as visceral activities, arousal, attention, and locomotion, but the specific roles of different ZI subdomains or cell types have not been well examined. Recent studies combining optogenetics, behavioral assays, neural tracing, and neural activity-recording reveal novel functional roles of ZI depending on specific input–output connectivity patterns. Here, we review these studies and summarize functions of ZI into four categories: sensory integration, behavioral output control, motivational drive, and neural plasticity. In view of these new findings, we propose that ZI serves as an integrative node for global modulation of behaviors and physiological states.

  • Reinventing Neuroaging Research in the Digital Age
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-14
    Matt J. Huentelman; Joshua S. Talboom; Candace R. Lewis; Zhao Chen; Carol A. Barnes

    The worldwide average human lifespan has increased over the past century. These changing demographics demand a reinvention of experimental approaches to study the brain and aging, with the aim of better matching cognitive healthspan with human lifespan. Past studies of cognitive aging included sample sizes that tended to be underpowered, were not sufficiently representative of national population characteristics, and often lacked longitudinal assessments. As a step to address these shortcomings, we propose a framework that encourages interaction between electronic-based and face-to-face study designs. We argue that this will achieve the necessary synergy to accelerate progress in the discovery and application of personalized interventions to optimize brain and cognitive health.

  • Fiery Cell Death: Pyroptosis in the Central Nervous System
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-13
    Brienne A. McKenzie; Vishva M. Dixit; Christopher Power

    Pyroptosis (‘fiery death’) is an inflammatory type of regulated cell death (RCD), which occurs downstream of inflammasome activation. Pyroptosis is mediated directly by the recently identified family of pore-forming proteins known as gasdermins, the best characterized of which is gasdermin D (GSDMD). Recent investigations implicate pyroptosis in the pathogenesis of multiple neurological diseases. In this review, we discuss molecular mechanisms that drive pyroptosis, evidence for pyroptosis within the CNS, and emerging therapeutic strategies for its inhibition in the context of neurological disease.

  • Are There Islands of Awareness?
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-10
    Tim Bayne, Anil K. Seth, Marcello Massimini

    Ordinary human experience is embedded in a web of causal relations that link the brain to the body and the wider environment. However, there might be conditions in which brain activity supports consciousness even when that activity is fully causally isolated from the body and its environment. Such cases would involve what we call islands of awareness: conscious states that are neither shaped by sensory input nor able to be expressed by motor output. This opinion article considers conditions in which such islands might occur, including ex cranio brains, hemispherotomy, and in cerebral organoids. We examine possible methods for detecting islands of awareness, and consider their implications for ethics and for the nature of consciousness.

  • Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-10
    Chinnakkaruppan Adaikkan, Li-Huei Tsai

    Studies have shown that gamma oscillations (30–100 Hz) are relevant for neurocircuit function, behavior, and memory. To examine a possible causal contribution of gamma oscillations to cognitive function, recent studies have employed various types of brain stimulation to induce gamma oscillations. Techniques such as optogenetics or sensory stimulation appear to engage canonical neurocircuits that encompass excitatory and inhibitory interneurons, similarly to those driven by sensory experience, to induce gamma entrainment. Sensory evoked gamma entrainment improves cognitive function in mouse models. Oscillations have traditionally been studied at the neurophysiological level; however, sensory evoked gamma entrainment is able to induce gene expression changes in multiple cell types including neurons and microglia. Furthermore, evidence suggests that chronic gamma entrainment offers neuroprotective effects.

  • Glucose-Sensing Neurons Reciprocally Regulate Insulin and Glucagon
    Trends Neurosci. (IF 12.314) Pub Date : 2019-12-05
    Zepeng Yao, Kristin Scott

    A recent paper by Oh et al. identified a single pair of neurons in the fruit fly brain that directly senses ‘blood’ glucose levels and reciprocally regulates the secretion of insulin and glucagon. This study provides insight into how the brain regulates the circulation and storage of glucose.

  • Neocortex–Cerebellum Circuits for Cognitive Processing
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-29
    Mark J. Wagner, Liqun Luo

    Although classically thought of as a motor circuit, the cerebellum is now understood to contribute to a wide variety of cognitive functions through its dense interconnections with the neocortex, the center of brain cognition. Recent investigations have shed light on the nature of cerebellar cognitive processing and information exchange with the neocortex. We review findings that demonstrate widespread reward-related cognitive input to the cerebellum, as well as new studies that have characterized the codependence of processing in the neocortex and cerebellum. Together, these data support a view of the neocortex–cerebellum circuit as a joint dynamic system both in classical sensorimotor contexts and reward-related, cognitive processing. These studies have also expanded classical theory on the computations performed by the cerebellar circuit.

  • Travelling Together: A Unifying Pathomechanism for ALS
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-16
    Pietro Fratta, Nicol Birsa, Andrew P. Tosolini, Giampietro Schiavo

    Axonal transport is critical for neuronal homeostasis and relies on motor complexes bound to cargoes via specific adaptors. However, the mechanisms responsible for the spatiotemporal regulation of axonal transport are not completely understood. A recent study by Liao et al. contributes to filling this gap by reporting that RNA granules ‘hitchhike’ on LAMP1-positive organelles using annexin A11 as a tether.

  • Editing the Epigenome to Tackle Brain Disorders
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-07
    X. Shawn Liu, Rudolf Jaenisch

    Genetic studies of epigenetic modifiers such as DNA methyltransferases and histone acetyltransferases have revealed a critical role for epigenetic regulation during brain development and function. Alteration of epigenetic modifications have been documented in a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative diseases. Development of epigenome editing tools enables a functional dissection of the link between altered epigenetic changes and disease outcomes. Here, we review the development of epigenome editing tools, summarize proof of concept applications focusing on brain disease-associated genes, and discuss the promising application and challenges of epigenome editing to tackle brain disorders.

  • Is There a Hemispheric Disconnect in Neurodevelopmental Disorders?
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-06
    Jacob Ellegood

    The CYFIP1 gene has been linked to autism and schizophrenia and, while there is a noted heterogeneity, both have been characterized to be disorders of connectivity. Recent studies by Dominquez-Iturza et al. and Silva et al. provide direct evidence for CYFIP1 in functional and structural connectivity in the brain.

  • Astroglia-Derived ATP Modulates CNS Neuronal Circuits
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-05
    Peter Illes, Geoffrey Burnstock, Yong Tang

    It is broadly recognized that ATP not only supports energy storage within cells but is also a transmitter/signaling molecule that serves intercellular communication. Whereas the fast (co)transmitter function of ATP in the peripheral nervous system has been convincingly documented, in the central nervous system (CNS) ATP appears to be primarily a slow transmitter/modulator. Data discussed in the present review suggest that the slow modulatory effects of ATP arise as a result of its vesicular/nonvesicular release from astrocytes. ATP acts together with other glial signaling molecules such as cytokines, chemokines, and free radicals to modulate neuronal circuits. Hence, astrocytes are positioned at the crossroads of the neuron–glia–neuron communication pathway.

  • Accumulators, Neurons, and Response Time
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-05
    Jeffrey D. Schall

    The marriage of cognitive neurophysiology and mathematical psychology to understand decision-making has been exceptionally productive. This interdisciplinary area is based on the proposition that particular neurons or circuits instantiate the accumulation of evidence specified by mathematical models of sequential sampling and stochastic accumulation. This linking proposition has earned widespread endorsement. Here, a brief survey of the history of the proposition precedes a review of multiple conundrums and paradoxes concerning the accuracy, precision, and transparency of that linking proposition. Correctly establishing how abstract models of decision-making are instantiated by particular neural circuits would represent a remarkable accomplishment in mapping mind to brain. Failing would reveal challenging limits for cognitive neuroscience. This is such a vigorous area of research because so much is at stake.

  • Lysosomal Dysfunction at the Centre of Parkinson’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-05
    Rebecca L. Wallings, Stewart W. Humble, Michael E. Ward, Richard Wade-Martins

    Parkinson’s disease (PD) and frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) are insidious and incurable neurodegenerative diseases that represent a significant burden to affected individuals, caregivers, and an ageing population. Both PD and FTD/ALS are defined at post mortem by the presence of protein aggregates and the loss of specific subsets of neurons. We examine here the crucial role of lysosome dysfunction in these diseases and discuss recent evidence for converging mechanisms. This review draws upon multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells (iPSCs), and animal models to argue that lysosomal failure is a primary mechanism of disease, rather than merely reflecting association with protein aggregate end-points. This review provides compelling rationale for targeting lysosomes in future therapeutics for both PD and FTD/ALS.

  • Looming Danger: Unraveling the Circuitry for Predator Threats
    Trends Neurosci. (IF 12.314) Pub Date : 2019-11-04
    Julieta E. Lischinsky, Dayu Lin

    Threat avoidance, particularly from predators, is key for survival. Through the use of optogenetics, viral tracing, and electrophysiological recordings, Zhou and colleagues identified a superior colliculus to ventral tegmental area pathway in detecting alarming visual cues and mediating defensive behaviors in mice. These findings provide novel insight into the neural circuit underlying innate predator defense.

  • Loss of normal huntingtin function: new developments in Huntington's disease research.
    Trends Neurosci. (IF 12.314) Pub Date : 2001-02-22
    E Cattaneo,D Rigamonti,D Goffredo,C Zuccato,F Squitieri,S Sipione

    Huntington's disease is characterized by a loss of brain striatal neurons that occurs as a consequence of an expansion of a CAG repeat in the huntingtin protein. The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the protein. Analysis of the mutant protein has attracted most of the research activity in the field, however re-examination of earlier data and new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology. Thus, complete elucidation of the physiological role(s) of huntingtin and its mode of action are essential and could lead to new therapeutic approaches.

  • Consolidation of motor memory.
    Trends Neurosci. (IF 12.314) Pub Date : 2005-11-18
    John W Krakauer,Reza Shadmehr

    An issue of great recent interest is whether motor memory consolidates in a manner analogous to declarative memory--that is, with the formation of a memory that progresses over time from a fragile state, which is susceptible to interference by a lesion or a conflicting motor task, to a stabilized state, which is resistant to such interference. Here, we first review studies that examine the anatomical basis for motor consolidation. Evidence implicates cerebellar circuitry in two types of associative motor learning--eyelid conditioning and vestibulo-ocular reflex adaptation--and implicates primary motor cortex in skilled finger movements. We also review evidence for and against a consolidation process for adaptation of arm movements. We propose that contradictions have arisen because consolidation can be masked by inhibition of memory retrieval.

  • Mitophagy and Alzheimer's Disease: Cellular and Molecular Mechanisms.
    Trends Neurosci. (IF 12.314) Pub Date : 2017-02-14
    Jesse S Kerr,Bryan A Adriaanse,Nigel H Greig,Mark P Mattson,M Zameel Cader,Vilhelm A Bohr,Evandro F Fang

    Neurons affected in Alzheimer's disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid beta peptide (Aβ) and Tau pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impair mitophagy. Interventions that bolster mitochondrial health and/or stimulate mitophagy may therefore forestall the neurodegenerative process in AD.

  • Resisting the Urge to Act: DREADDs Modifying Habits.
    Trends Neurosci. (IF 12.314) Pub Date : 2017-01-21
    Mark A G Eldridge,Barry J Richmond

    Recently, Meyer and Bucci used chemogenetic technology - artificial excitatory and inhibitory receptors - to modulate neuronal activity in two connected brain regions in opposite directions simultaneously. This innovative manipulation revealed that the two regions studied, orbitofrontal cortex and nucleus accumbens, are not sequentially dependent during contextual decision-making.

  • Sonic Hedgehog Signaling and Hippocampal Neuroplasticity.
    Trends Neurosci. (IF 12.314) Pub Date : 2016-11-21
    Pamela J Yao,Ronald S Petralia,Mark P Mattson

    Sonic hedgehog (Shh) is a secreted protein that controls the patterning of neural progenitor cells, and their neuronal and glial progeny, during development. Emerging findings suggest that Shh also has important roles in the formation and plasticity of neuronal circuits in the hippocampus, a brain region of fundamental importance in learning and memory. Shh mediates activity-dependent and injury-induced hippocampal neurogenesis. Activation of Shh receptors in the dendrites of hippocampal neurons engages a trans-neuronal signaling pathway that accelerates axon outgrowth and enhances glutamate release from presynaptic terminals. Impaired Shh signaling may contribute to the pathogenesis of several developmental and adult-onset neurological disorders that affect the hippocampus, suggesting a potential for therapeutic interventions that target Shh pathways.

  • There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases.
    Trends Neurosci. (IF 12.314) Pub Date : 2016-02-24
    Sebastien Paillusson,Radu Stoica,Patricia Gomez-Suaga,Dawn H W Lau,Sarah Mueller,Tanya Miller,Christopher C J Miller

    Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis with associated frontotemporal dementia (ALS/FTD) are major neurodegenerative diseases for which there are no cures. All are characterised by damage to several seemingly disparate cellular processes. The broad nature of this damage makes understanding pathogenic mechanisms and devising new treatments difficult. Can the different damaged functions be linked together in a common disease pathway and which damaged function should be targeted for therapy? Many functions damaged in neurodegenerative diseases are regulated by communications that mitochondria make with a specialised region of the endoplasmic reticulum (ER; mitochondria-associated ER membranes or 'MAM'). Moreover, several recent studies have shown that disturbances to ER-mitochondria contacts occur in neurodegenerative diseases. Here, we review these findings.

  • New neurons in the adult striatum: from rodents to humans.
    Trends Neurosci. (IF 12.314) Pub Date : 2015-08-25
    Dragos Inta,Heather A Cameron,Peter Gass

    Most neurons are generated during development and are not replaced during adulthood, even if they are lost to injury or disease. However, it is firmly established that new neurons are generated in the dentate gyrus of the hippocampus of almost all adult mammals, including humans. Nevertheless, many questions remain regarding adult neurogenesis in other brain regions and particularly in humans, where standard birth-dating methods are not generally feasible. Exciting recent evidence indicates that calretinin-expressing interneurons are added to the adult human striatum at a substantial rate. The role of new neurons is unknown, but studies in rodents will be able to further elucidate their identity and origin and then we may begin to understand their regulation and function.

  • Memory trace replay: the shaping of memory consolidation by neuromodulation.
    Trends Neurosci. (IF 12.314) Pub Date : 2015-08-16
    Laura A Atherton,David Dupret,Jack R Mellor

    The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed.

  • Impaired intracellular trafficking defines early Parkinson's disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2015-02-03
    Benjamin H M Hunn,Stephanie J Cragg,J Paul Bolam,Maria-Grazia Spillantini,Richard Wade-Martins

    Parkinson's disease (PD) is an insidious and incurable neurodegenerative disease, and represents a significant cost to individuals, carers, and ageing societies. It is defined at post-mortem by the loss of dopamine neurons in the substantia nigra together with the presence of Lewy bodies and Lewy neurites. We examine here the role of α-synuclein and other cellular transport proteins implicated in PD and how their aberrant activity may be compounded by the unique anatomy of the dopaminergic neuron. This review uses multiple lines of evidence from genetic studies, human tissue, induced pluripotent stem cells, and refined animal models to argue that prodromal PD can be defined as a disease of impaired intracellular trafficking. Dysfunction of the dopaminergic synapse heralds trafficking impairment.

  • Presynaptic long-term depression mediated by Gi/o-coupled receptors.
    Trends Neurosci. (IF 12.314) Pub Date : 2014-08-28
    Brady K Atwood,David M Lovinger,Brian N Mathur

    Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for the regulation of information storage and the control of actions, as well as for synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA-type glutamate receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity, the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a 'common pathway' are described. We review here the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate whether all Gi/o-GPCRs are capable of inducing presynaptic LTD.

  • Working together: basal ganglia pathways in action selection.
    Trends Neurosci. (IF 12.314) Pub Date : 2014-05-13
    Danielle M Friend,Alexxai V Kravitz

    Jin, Tecuapetla, and Costa combined in vivo electrophysiology with optogenetic-identification to examine firing in multiple basal ganglia nuclei during rapid motor sequences. Their results support a model of basal ganglia function in which co-activation of the direct and indirect pathways facilitate appropriate, while inhibiting competing, motor programs.

  • Telomere shortening in neurological disorders: an abundance of unanswered questions.
    Trends Neurosci. (IF 12.314) Pub Date : 2014-04-05
    Erez Eitan,Emmette R Hutchison,Mark P Mattson

    Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimer's and Parkinson's patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and individuals. Additional research is needed to determine whether neuronal and glial telomeres shorten during aging and in neurodegenerative disorders, if and how LTL is related to brain cell telomere shortening, and whether telomere shortening plays a causal role in or exacerbates neurological disorders.

  • Diversity of astroglial functions alludes to subcellular specialisation.
    Trends Neurosci. (IF 12.314) Pub Date : 2014-03-19
    Dmitri A Rusakov,Lucie Bard,Michael G Stewart,Christian Henneberger

    Rapid signal exchange between astroglia and neurons has emerged as an essential element of neural circuits of the brain. However, the increasing variety of mechanisms contributing to this signalling appears to be facing a conceptual stalemate. The communication medium of astroglia involves intracellular [Ca(2+)] waves, which until recently have been associated with slow, global [Ca(2+)] rises. How such a uniform trigger could handle fast and diverse molecular messages remains unexplained. Recent studies have, however, revealed a variety of apparently independent Ca(2+) activities within individual astrocytic compartments, also indicating the prevalence of subcellular segregation for some signalling mechanisms. These signs of intracellular compartmentalisation might provide the key to the multitude of adaptive roles played by astroglia.

  • What do grid cells contribute to place cell firing?
    Trends Neurosci. (IF 12.314) Pub Date : 2014-02-04
    Daniel Bush,Caswell Barry,Neil Burgess

    The unitary firing fields of hippocampal place cells are commonly assumed to be generated by input from entorhinal grid cell modules with differing spatial scales. Here, we review recent research that brings this assumption into doubt. Instead, we propose that place cell spatial firing patterns are determined by environmental sensory inputs, including those representing the distance and direction to environmental boundaries, while grid cells provide a complementary self-motion related input that contributes to maintaining place cell firing. In this view, grid and place cell firing patterns are not successive stages of a processing hierarchy, but complementary and interacting representations that work in combination to support the reliable coding of large-scale space.

  • Molecular neuroanatomy: a generation of progress.
    Trends Neurosci. (IF 12.314) Pub Date : 2014-01-07
    Jonathan D Pollock,Da-Yu Wu,John S Satterlee

    The neuroscience research landscape has changed dramatically over the past decade. Specifically, an impressive array of new tools and technologies have been generated, including but not limited to: brain gene expression atlases, genetically encoded proteins to monitor and manipulate neuronal activity, and new methods for imaging and mapping circuits. However, despite these technological advances, several significant challenges must be overcome to enable a better understanding of brain function and to develop cell type-targeted therapeutics to treat brain disorders. This review provides an overview of some of the tools and technologies currently being used to advance the field of molecular neuroanatomy, and also discusses emerging technologies that may enable neuroscientists to address these crucial scientific challenges over the coming decade.

  • Reflections on agranular architecture: predictive coding in the motor cortex.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-10-26
    Stewart Shipp,Rick A Adams,Karl J Friston

    The agranular architecture of motor cortex lacks a functional interpretation. Here, we consider a 'predictive coding' account of this unique feature based on asymmetries in hierarchical cortical connections. In sensory cortex, layer 4 (the granular layer) is the target of ascending pathways. We theorise that the operation of predictive coding in the motor system (a process termed 'active inference') provides a principled rationale for the apparent recession of the ascending pathway in motor cortex. The extension of this theory to interlaminar circuitry also accounts for a sub-class of 'mirror neuron' in motor cortex--whose activity is suppressed when observing an action--explaining how predictive coding can gate hierarchical processing to switch between perception and action.

  • Cytoplasmic dynein heavy chain: the servant of many masters.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-09-17
    Giampietro Schiavo,Linda Greensmith,Majid Hafezparast,Elizabeth M C Fisher

    Cytoplasmic dynein is the main retrograde motor in all eukaryotic cells. This complex comprises different subunits assembled on a cytoplasmic dynein heavy chain 1 (DYNC1H1) dimer. Cytoplasmic dynein is particularly important for neurons because it carries essential signals and organelles from distal sites to the cell body. In the past decade, several mouse models have helped to dissect the numerous functions of DYNC1H1. Additionally, several DYNC1H1 mutations have recently been found in human patients that give rise to a broad spectrum of developmental and midlife-onset disorders. Here, we discuss the effects of mutations of mouse and human DYNC1H1 and how these studies are giving us new insight into the many critical roles DYNC1H1 plays in the nervous system.

  • Molecular nexopathies: a new paradigm of neurodegenerative disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-07-24
    Jason D Warren,Jonathan D Rohrer,Jonathan M Schott,Nick C Fox,John Hardy,Martin N Rossor

    Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with 'molecular nexopathies': specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types (e.g., clustered versus distributed connections) to particular pathogenic proteins; and differential impact of molecular effects (e.g., toxic-gain-of-function versus loss-of-function) on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology.

  • Spikes and ribbon synapses in early vision.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-05-28
    Tom Baden,Thomas Euler,Matti Weckström,Leon Lagnado

    Image processing begins in the retina, where neurons respond with graded voltage changes that must be converted into spikes. This conversion from 'analog' to 'digital' coding is a fundamental transformation carried out by the visual system, but the mechanisms are still not well understood. Recent work demonstrates that, in vertebrates, graded-to-spiking conversion of the visual signal begins in the axonal system of bipolar cells (BCs), which transmit visual information through ribbon-type synapses specialized for responding to graded voltage signals. Here, we explore the evidence for and against the idea that ribbon synapses also transmit digital information. We then discuss the potential costs and benefits of digitization at different stages of visual pathways in vertebrates and invertebrates.

  • How to erase memory traces of pain and fear.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-04-23
    Jürgen Sandkühler,Jonathan Lee

    Pain and fear are both aversive experiences that strongly impact on behaviour and well being. They are considered protective when they lead to meaningful, adaptive behaviour such as the avoidance of situations that are potentially dangerous to the integrity of tissue (pain) or the individual (fear). Pain and fear may, however, become maladaptive if expressed under inappropriate conditions or at excessive intensities for extended durations. Currently emerging concepts of maladaptive pain and fear suggest that basic neuronal mechanisms of memory formation are relevant for the development of pathological forms of pain and fear. Thus, the processes of erasing memory traces of pain and fear may constitute promising targets for future therapies.

  • Development of human embryonic stem cell therapies for age-related macular degeneration.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-04-23
    Amanda-Jayne F Carr,Matthew J K Smart,Conor M Ramsden,Michael B Powner,Lyndon da Cruz,Peter J Coffey

    Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults and ultimately leads to the death of photoreceptor cells in the macular area of the neural retina. Currently, treatments are only available for patients with the wet form of AMD. In this review, we describe recent approaches to develop cell-based therapies for the treatment of AMD. Recent research has focused on replacing the retinal pigment epithelium (RPE), a monolayer of cells vital to photoreceptor cell health. We discuss the various methods used to differentiate and purify RPE from human embryonic stem cells (HESC), and describe the surgical approaches being used to transplant these cells in existing and forthcoming clinical trials.

  • Hypothalamic clocks and rhythms in feeding behaviour.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-01-22
    David A Bechtold,Andrew S I Loudon

    Daily rhythms are evident across our physiology, ranging from overt behavioural patterns like sleep to intricate molecular rhythms in epigenetic coding. Driving these rhythms at an anatomical and cellular level are circadian clock networks comprising core clock genes and an ever-expanding list of clock-controlled genes. Research over the past decade has revealed an intimate relationship between the clockwork and metabolic processes. In line with this, feeding behaviour in many species exhibits a strong circadian rhythm and, when restricted, food becomes the most potent entraining stimulus for clocks of the body. Critically, there are several indications that disturbance of our daily rhythms contributes to the development of obesity and diabetes. Given our 24-h society, it is important that we understand how the circadian clock influences what and when we eat.

  • Hypothalamic tanycytes: potential roles in the control of feeding and energy balance.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-01-22
    Matei Bolborea,Nicholas Dale

    Tanycytes, glial-like cells that line the third ventricle, are emerging as components of the hypothalamic networks that control body weight and energy balance. They contact the cerebrospinal fluid (CSF) and send processes that come into close contact with neurons in the arcuate and ventromedial hypothalamic nuclei. Tanycytes are glucosensitive and are able to respond to transmitters associated with arousal and the drive to feed. At least some tanycytes are stem cells and, in the median eminence, may be stimulated by diet to generate new neurons. The quest is on to understand how tanycytes detect and respond to changes in energy balance and how they communicate with the rest of the nervous system to effect their functions.

  • Adenosine: setting the stage for plasticity.
    Trends Neurosci. (IF 12.314) Pub Date : 2013-01-22
    Raquel B Dias,Diogo M Rombo,Joaquim A Ribeiro,Jeremy M Henley,Ana M Sebastião

    It is widely accepted that Hebbian forms of plasticity mediate selective modifications in synaptic strength underlying information encoding in response to experience and circuit formation or refinement throughout development. Several complementary forms of homeostatic plasticity coordinate to keep Hebbian plasticity in check, frequently through the actions of conserved regulatory molecules. Recent evidence suggests that this may be the case for adenosine, which is ubiquitous in the brain and is released by both neurons and glial cells via constitutive and activity-dependent mechanisms. Through A1 and A2A receptor activation, adenosine modulates neuronal homeostasis and tunes the ability of synapses to undergo and/or sustain plasticity. Here, we review how adenosine equilibrates neuronal activity and sets the stage for synaptic plasticity.

  • Individual differences in recovery from traumatic fear.
    Trends Neurosci. (IF 12.314) Pub Date : 2012-12-25
    Andrew Holmes,Nicolas Singewald

    Although exposure to major psychological trauma is unfortunately common, risk for related neuropsychiatric conditions, such as post-traumatic stress disorder (PTSD), varies greatly among individuals. Fear extinction offers a tractable and translatable behavioral readout of individual differences in learned recovery from trauma. Studies in rodent substrains and subpopulations are providing new insights into neural system dysfunctions associated with impaired fear extinction. Rapid progress is also being made in identifying key molecular circuits, epigenetic mechanisms, and gene variants associated with differences in fear extinction. Here, we discuss how this research is informing understanding of the etiology and pathophysiology of individual differences in risk for trauma-related anxiety disorders, and how future work can help identify novel diagnostic biomarkers and pharmacotherapeutics for these disorders.

  • The sigma-1 receptor: roles in neuronal plasticity and disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2012-10-30
    Saïd Kourrich,Tsung-Ping Su,Michiko Fujimoto,Antonello Bonci

    Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)-mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca(2+) signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases.

  • Nerve dependence in tissue, organ, and appendage regeneration.
    Trends Neurosci. (IF 12.314) Pub Date : 2012-09-20
    Anoop Kumar,Jeremy P Brockes

    Many regeneration contexts require the presence of regenerating nerves as a transient component of the progenitor cell niche. Here we review nerve involvement in regeneration of various structures in vertebrates and invertebrates. Nerves are also implicated as persistent determinants in the niche of certain stem cells in mammals, as well as in Drosophila. We consider our present understanding of the cellular and molecular mechanisms underlying nerve dependence, including evidence of critical interactions with glia and non-neural cell types. The example of the salamander aneurogenic limb illustrates that developmental interactions between the limb bud and its innervation can be determinative for adult regeneration. These phenomena provide a different perspective on nerve cells to that based on chemical and electrical excitability.

  • The dystrophin-glycoprotein complex in brain development and disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2012-05-26
    Adrian Waite,Susan C Brown,Derek J Blake

    In addition to muscle disease, defects in processing and assembly of the dystrophin-glycoprotein complex (DGC) are associated with a spectrum of brain abnormalities ranging from mild cognitive impairment (MCI) to neuronal migration disorders. In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. During development, defects in the glycosylation of α-dystroglycan that impair its ability to interact with the extracellular matrix (ECM) are frequently associated with cobblestone lissencephaly and mental retardation. Furthermore, mutations in the gene encoding ɛ-sarcoglycan (SGCE) cause the neurogenic movement disorder myoclonus dystonia syndrome. In this review, we describe recent progress in defining distinct roles for the DGC in neurons and glia.

  • Mitochondria as a central sensor for axonal degenerative stimuli.
    Trends Neurosci. (IF 12.314) Pub Date : 2012-05-15
    Felipe A Court,Michael P Coleman

    Axonal degeneration is a major contributor to neuronal dysfunction in many neurological conditions and has additional roles in development. It can be triggered by divergent stimuli including mechanical, metabolic, infectious, toxic, hereditary and inflammatory stresses. Axonal mitochondria are an important convergence point as regulators of bioenergetic metabolism, reactive oxygen species (ROS), Ca²⁺ homeostasis and protease activation. The challenges likely to render axonal mitochondria more vulnerable than their cellular counterparts are reviewed, including axonal transport, replenishing nuclear-encoded proteins and maintenance of quality control, fusion and fission in locations remote from the cell body. The potential for mitochondria to act as a decision node in axon loss is considered, highlighting the need to understand the biology of axonal mitochondria and their contributions to degenerative mechanisms for novel therapeutic strategies.

  • The neurodevelopmental origins of suicidal behavior.
    Trends Neurosci. (IF 12.314) Pub Date : 2011-12-20
    Gustavo Turecki,Carl Ernst,Fabrice Jollant,Benoit Labonté,Naguib Mechawar

    Suicide and related behaviors are complex phenomena associated with different risk factors. Although most individuals who display suicidal behavior do not have a history of early-life adversity, a significant minority does. Recent animal and human data have suggested that early-life adversity leads to epigenetic regulation of genes involved in stress-response systems. Here, we review this evidence and suggest that early-life adversity increases risk of suicide in susceptible individuals by influencing the development of stable emotional, behavioral and cognitive phenotypes that are likely to result from the epigenetic regulation of the hypothalamic-pituitary-adrenal axis and other systems involved in responses to stress.

  • New insights into the relationship between dopamine, beta oscillations and motor function.
    Trends Neurosci. (IF 12.314) Pub Date : 2011-10-25
    Ned Jenkinson,Peter Brown

    Synchronised neuronal oscillations at beta frequencies are prevalent in the human motor system, but their function is unclear. In this Opinion article, we propose that the levels of beta oscillations provide a measure of the likelihood that a new voluntary action will need to be actuated. Oscillatory beta activity is in turn modulated by net dopamine levels at sites of cortical input to the basal ganglia. We hypothesise that net dopamine levels are modulated in response to salient internal and external cues. Crucially, the resulting modulation of beta activity is predictive, enabling the appropriate prospective resourcing and preparation of potential actions. Loss of dopamine, as in Parkinson's disease, annuls this function, unless net dopaminergic activity can be elevated through medication.

  • Updating hippocampal representations: CA2 joins the circuit.
    Trends Neurosci. (IF 12.314) Pub Date : 2011-09-02
    Matthew W Jones,Thomas J McHugh

    The hippocampus integrates the encoding, storage and recall of memories, binding the spatio-temporal and sensory information that constitutes experience and keeping episodes in their correct context. The rapid and accurate processing of such daunting volumes of continuously changing data relies on dynamically assigning different aspects of mnemonic processing to specialized, interconnected networks corresponding to the anatomical subfields of dentate gyrus (DG), CA3 and CA1. However, differentially processed information ultimately has to be reintegrated into conjunctive representations, and this is unlikely to be achieved by unidirectional, sequential steps through a DG-CA3-CA1 loop. In this Review, we highlight recently discovered anatomical and physiological features that are likely to necessitate updates to the hippocampal circuit diagram, particularly by incorporating the oft-neglected CA2 region.

  • Neurobiology of the incubation of drug craving.
    Trends Neurosci. (IF 12.314) Pub Date : 2011-07-19
    Charles L Pickens,Mikko Airavaara,Florence Theberge,Sanya Fanous,Bruce T Hope,Yavin Shaham

    It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the past decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering understanding of brain mechanisms and circuits that underlie craving and relapse in human addicts.

  • Toll-like receptor signaling in neural plasticity and disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2011-03-23
    Eitan Okun,Kathleen J Griffioen,Mark P Mattson

    Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands. TLR signaling in immune cells, glia and neurons can play roles in the pathogenesis of stroke, Alzheimer's disease (AD) and multiple sclerosis (MS). Recent findings suggest that TLR signaling also influences multiple dynamic processes in the developing and adult central nervous system including neurogenesis, axonal growth and structural plasticity. In addition, TLRs are implicated in the regulation of behaviors including learning, memory and anxiety. This review describes recently discovered and unexpected roles for TLRs in neuroplasticity, and the implications of these findings for future basic and translational research studies.

  • Tuning of synaptic responses: an organizing principle for optimization of neural circuits.
    Trends Neurosci. (IF 12.314) Pub Date : 2010-11-12
    Cian O'Donnell,Matthew F Nolan

    Neuron types are classically defined by anatomical and physiological properties that determine how synaptic inputs are integrated. Here, we provide an overview of the evidence that, among neurons of a single type, integration of synaptic responses is further tuned according to the particular function that individual neurons carry out. Recent data suggest that tuning of synaptic responses is not restricted to sensory pathways, but extends to cognitive and motor circuits. We propose that tuning of synaptic integration results from general cellular mechanisms for optimization of information processing that are distinct from, but complementary to, homeostasis and memory storage. These cellular tuning mechanisms might be crucial for distributed computations underlying sensory, motor and cognitive functions.

  • α-Synuclein and dopamine at the crossroads of Parkinson's disease.
    Trends Neurosci. (IF 12.314) Pub Date : 2010-10-22
    Lara Lourenço Venda,Stephanie J Cragg,Vladimir L Buchman,Richard Wade-Martins

    α-Synuclein is central to the Lewy body neuropathology of Parkinson's disease (PD), a devastating neurodegenerative disorder characterized by numerous motor and non-motor manifestations. The cardinal motor symptoms are linked to death of dopaminergic neurons in the nigrostriatal pathway. Here we ask why these neurons are preferentially susceptible to neurodegeneration in PD and how α-synuclein is involved. To address these questions we bring together recent findings from genome-wide association studies, which reveal the involvement of α-synuclein gene variants in sporadic PD, with recent studies highlighting important roles for α-synuclein in synaptic transmission and dopaminergic neuron physiology. These latest advances add to our understanding of PD etiology and provide a central link between the genetic findings and neurodegeneration observed in sporadic PD.

  • Functional localization within the prefrontal cortex: missing the forest for the trees?
    Trends Neurosci. (IF 12.314) Pub Date : 2010-09-25
    Charles R E Wilson,David Gaffan,Philip G F Browning,Mark G Baxter

    Anatomical and functional studies of the prefrontal cortex (PFC) have identified multiple PFC subregions. We argue that the PFC is involved in cognitive functions exceeding the sum of specific functions attributed to its subregions. These can be revealed either by lesions of the whole PFC, or more specifically by selective disconnection of the PFC from certain types of information (for example, visual) allowing the investigation of PFC function in toto. Recent studies in macaque monkeys using the latter approach lead to a second conclusion: that the PFC, as a whole, could be fundamentally specialized for representing events that are extended in time. The representation of temporally complex events might underlie PFC involvement in general intelligence, decision-making, and executive function.

  • Building a bridal chamber: development of the thalamus.
    Trends Neurosci. (IF 12.314) Pub Date : 2010-06-15
    Steffen Scholpp,Andrew Lumsden

    The thalamus is a central brain region that plays a crucial role in distributing incoming sensory information to appropriate regions of the cortex. The thalamus develops in the posterior part of the embryonic forebrain, where early cell fate decisions are controlled by a local signaling center - the mid-diencephalic organizer - which forms at the boundary between prospective prethalamus and thalamus. In this review we discuss recent observations of early thalamic development in zebrafish, chick, and mouse embryos, that reveal a conserved set of interactions between homeodomain transcription factors. These interactions position the organizer along the neuraxis. The most prominent of the organizer's signals, Sonic hedgehog, is necessary for conferring regional identity on the prethalamus and thalamus and for patterning their differentiation.

  • The propagation of prion-like protein inclusions in neurodegenerative diseases.
    Trends Neurosci. (IF 12.314) Pub Date : 2010-05-25
    Michel Goedert,Florence Clavaguera,Markus Tolnay

    The most common neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the misfolding of a small number of proteins that assemble into ordered aggregates in affected brain cells. For many years, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. Recent research has now shown that cell non-autonomous mechanisms are also important for the pathogenesis of neurodegenerative diseases with intracellular filamentous inclusions. The intercellular transfer of inclusions made of tau, alpha-synuclein, huntingtin and superoxide dismutase 1 has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system.

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上海纽约大学William Glover