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  • Probing the Link Between Perception and Oscillations: Lessons from Transcranial Alternating Current Stimulation
    Neuroscientist (IF 7.461) Pub Date : 2019-02-07
    Yuranny Cabral-Calderin; Melanie Wilke

    Brain oscillations are regarded as important for perception as they open and close time windows for neural spiking to enable the effective communication within and across brain regions. In the past, studies on perception primarily relied on the use of electrophysiological techniques for probing a correlative link between brain oscillations and perception. The emergence of noninvasive brain stimulation techniques such as transcranial alternating current stimulation (tACS) provides the possibility to study the causal contribution of specific oscillatory frequencies to perception. Here, we review the studies on visual, auditory, and somatosensory perception that employed tACS to probe the causality of brain oscillations for perception. The current literature is consistent with a causal role of alpha and gamma oscillations in parieto-occipital regions for visual perception and theta and gamma oscillations in auditory cortices for auditory perception. In addition, the sensory gating by alpha oscillations applies not only to the visual but also to the somatosensory domain. We conclude that albeit more refined perceptual paradigms and individualized stimulation practices remain to be systematically adopted, tACS is a promising tool for establishing a causal link between neural oscillations and perception.

  • The Legacy of Rita Levi-Montalcini: From Nerve Growth Factor to Neuroinflammation
    Neuroscientist (IF 7.461) Pub Date : 2019-01-30
    Domenico Chirchiglia; Pasquale Chirchiglia; Dorotea Pugliese; Rosa Marotta

    Rita Levi-Montalcini was an extraordinary personality and with her profession she made a tremendous contribution to humanity. Doctor, Nobel laureate for medicine, neuroscientist, she contributed, thanks to her research, to improve the knowledge of the nervous system. She discovered the nerve growth factor, which is applied in various fields of neurology, concerning neurodegenerative diseases. She also studied, in relatively newer years, the mechanisms of neuroinflammation. This last is a research that has been developing in recent years and is based on the predominantly anti-inflammatory properties of endogenous substances that able to act not only on diseases of the nerves, neuropathies, on the nerve roots, and radiculopathies but also on migraine and other non-neurological diseases. Her long life was full of positive and negative events. Born in a Jewish family, she lived her life as a young woman through war, Nazi deportations, and the Holocaust. Despite the difficulties, she found time to do research in the medical field, organizing research laboratories with other scholars. She had a difficult life, interspread with pain, destruction, extermination of human beings but also rewarded by scientific discoveries. A “small” woman but a great neuroscientist.

  • The Striatum’s Role in Executing Rational and Irrational Economic Behaviors
    Neuroscientist (IF 7.461) Pub Date : 2019-01-24
    Ian J. Bamford; Nigel S. Bamford

    The striatum is a critical component of the brain that controls motor, reward, and executive function. This ancient and phylogenetically conserved structure forms a central hub where rapid instinctive, reflexive movements and behaviors in response to sensory stimulation or the retrieval of emotional memory intersect with slower planned motor movements and rational behaviors. This review emphasizes two distinct pathways that begin in the thalamus and converge in the striatum to differentially affect movements, behaviors, and decision making. The convergence of excitatory glutamatergic activity from the thalamus and cortex, along with dopamine release in response to novel stimulation, provide the basis for motor learning, reward seeking, and habit formation. We outline how the rules derived through research on neural pathways may enhance the predictability of reflexive actions and rational responses studied in behavioral economics.

  • Dentate Gyrus Immaturity in Schizophrenia
    Neuroscientist (IF 7.461) Pub Date : 2019-01-24
    Ayda Tavitian; Wei Song; Hyman M. Schipper

    Hippocampal abnormalities have been heavily implicated in the pathophysiology of schizophrenia. The dentate gyrus of the hippocampus was shown to manifest an immature molecular profile in schizophrenia subjects, as well as in various animal models of the disorder. In this position paper, we advance a hypothesis that this immature molecular profile is accompanied by an identifiable immature morphology of the dentate gyrus granule cell layer. We adduce evidence for arrested maturation of the dentate gyrus in the human schizophrenia-affected brain, as well as multiple rodent models of the disease. Implications of this neurohistopathological signature for current theory regarding the development of schizophrenia are discussed.

  • Neurocognitive and Perceptual Processing in Genetic Mouse Models of Schizophrenia: Emerging Lessons
    Neuroscientist (IF 7.461) Pub Date : 2019-01-17
    Anastasia Diamantopoulou; Joseph A. Gogos

    During the past two decades, the number of animal models of psychiatric disorders has grown exponentially. Of these, genetic animal models that are modeled after rare but highly penetrant mutations hold great promise for deciphering critical molecular, synaptic, and neurocircuitry deficits of major psychiatric disorders, such as schizophrenia. Animal models should aim to focus on core aspects rather than capture the entire human disease. In this context, animal models with strong etiological validity, where behavioral and neurophysiological phenotypes and the features of the disease being modeled are in unambiguous homology, are being used to dissect both elementary and complex cognitive and perceptual processing deficits present in psychiatric disorders at the level of neurocircuitry, shedding new light on critical disease mechanisms. Recent progress in neuroscience along with large-scale initiatives that propose a consistent approach in characterizing these deficits across different laboratories will further enhance the efficacy of these studies that will ultimately lead to identifying new biological targets for drug development.

  • CNS Injury: Posttranslational Modification of the Tau Protein as a Biomarker
    Neuroscientist (IF 7.461) Pub Date : 2017-11-22
    Mitchell T. Caprelli; Andrea J. Mothe; Charles H. Tator

    The ideal biomarker for central nervous system (CNS) trauma in patients would be a molecular marker specific for injured nervous tissue that would provide a consistent and reliable assessment of the presence and severity of injury and the prognosis for recovery. One candidate biomarker is the protein tau, a microtubule-associated protein abundant in the axonal compartment of CNS neurons. Following axonal injury, tau becomes modified primarily by hyperphosphorylation of its various amino acid residues and cleavage into smaller fragments. These posttrauma products can leak into the cerebrospinal fluid or bloodstream and become candidate biomarkers of CNS injury. This review examines the primary molecular changes that tau undergoes following traumatic brain injury and spinal cord injury, and reviews the current literature in traumatic CNS biomarker research with a focus on the potential for hyperphosphorylated and cleaved tau as sensitive biomarkers of injury.

  • Noncoding RNAs and Stroke
    Neuroscientist (IF 7.461) Pub Date : 2018-04-11
    Xuejing Zhang; Milton H. Hamblin; Ke-Jie Yin

    Over many years, extensive efforts have focused on the development and improvement of diagnostic and therapeutic strategies to reduce stroke-associated neurovascular damage, such as blood-brain barrier dysfunction, brain edema, parenchymal inflammation, and neural cell death. However, the only clinically applied pharmacological therapy to date for the treatment of acute ischemic stroke is thrombolysis. Because of the short therapeutic window of current thrombolytic therapy and the activation of various pathophysiological signaling cascades triggered after ischemic stroke, the development of new therapies is urgently required. Noncoding RNAs (ncRNAs) are defined as untranslated regulatory RNA molecules. Although ncRNAs with biological roles have been known for almost 60 years, they have within the past decade emerged as key mediators of posttranscriptional gene expression/function in pathological aspects of ischemic stroke. With properties of relative stability, specificity, and reproducibility, ncRNAs are considered to be promising as biomarkers and better candidates than proteins and genes for early recognition of the onset of disease. In this update, we summarized the current knowledge for three groups of ncRNAs in stroke, focusing on the role of long noncoding RNAs and circular RNAs as biomarkers for stroke and as targets for regulating large sets of genes in related pathways after ischemic stroke.

  • Dendritic Spine Elimination: Molecular Mechanisms and Implications
    Neuroscientist (IF 7.461) Pub Date : 2018-05-02
    Ivar S. Stein; Karen Zito

    Dynamic modification of synaptic connectivity in response to sensory experience is a vital step in the refinement of brain circuits as they are established during development and modified during learning. In addition to the well-established role for new spine growth and stabilization in the experience-dependent plasticity of neural circuits, dendritic spine elimination has been linked to improvements in learning, and dysregulation of spine elimination has been associated with intellectual disability and behavioral impairment. Proper brain function requires a tightly regulated balance between spine formation and spine elimination. Although most studies have focused on the mechanisms of spine formation, considerable progress has been made recently in delineating the neural activity patterns and downstream molecular mechanisms that drive dendritic spine elimination. Here, we review the current state of knowledge concerning the signaling pathways that drive dendritic spine shrinkage and elimination in the cerebral cortex and we discuss their implication in neuropsychiatric and neurodegenerative disease.

  • The Subthalamic Nucleus: Unravelling New Roles and Mechanisms in the Control of Action
    Neuroscientist (IF 7.461) Pub Date : 2018-03-20
    Tora Bonnevie; Kareem A. Zaghloul

    How do we decide what we do? This is the essence of action control, the process of selecting the most appropriate response among multiple possible choices. Suboptimal action control can involve a failure to initiate or adapt actions, or conversely it can involve making actions impulsively. There has been an increasing focus on the specific role of the subthalamic nucleus (STN) in action control. This has been fueled by the clinical relevance of this basal ganglia nucleus as a target for deep brain stimulation (DBS), primarily in Parkinson’s disease but also in obsessive-compulsive disorder. The context of DBS has opened windows to study STN function in ways that link neuroscientific and clinical fields closely together, contributing to an exceptionally high level of two-way translation. In this review, we first outline the role of the STN in both motor and nonmotor action control, and then discuss how these functions might be implemented by neuronal activity in the STN. Gaining a better understanding of these topics will not only provide important insights into the neurophysiology of action control but also the pathophysiological mechanisms relevant for several brain disorders and their therapies.

  • Exercise-Induced Neuroplasticity: A Mechanistic Model and Prospects for Promoting Plasticity
    Neuroscientist (IF 7.461) Pub Date : 2018-04-21
    Jenin El-Sayes; Diana Harasym; Claudia V. Turco; Mitchell B. Locke; Aimee J. Nelson

    Aerobic exercise improves cognitive and motor function by inducing neural changes detected using molecular, cellular, and systems level neuroscience techniques. This review unifies the knowledge gained across various neuroscience techniques to provide a comprehensive profile of the neural mechanisms that mediate exercise-induced neuroplasticity. Using a model of exercise-induced neuroplasticity, this review emphasizes the sequence of neural events that accompany exercise, and ultimately promote changes in human performance. This is achieved by differentiating between neuroplasticity induced by acute versus chronic aerobic exercise. Furthermore, this review emphasizes experimental considerations that influence the opportunity to observe exercise-induced neuroplasticity in humans. These include modifiable factors associated with the exercise intervention and nonmodifiable factors such as biological sex, ovarian hormones, genetic variations, and fitness level. To maximize the beneficial effects of exercise in health, disease, and following injury, future research should continue to explore the mechanisms that mediate exercise-induced neuroplasticity. This review identifies some fundamental gaps in knowledge that may serve to guide future research in this area.

  • Tracking Neuronal Connectivity from Electric Brain Signals to Predict Performance
    Neuroscientist (IF 7.461) Pub Date : 2018-05-20
    Fabrizio Vecchio; Francesca Miraglia; Paolo Maria Rossini

    The human brain is a complex container of interconnected networks. Network neuroscience is a recent venture aiming to explore the connection matrix built from the human brain or human “Connectome.” Network-based algorithms provide parameters that define global organization of the brain; when they are applied to electroencephalographic (EEG) signals network, configuration and excitability can be monitored in millisecond time frames, providing remarkable information on their instantaneous efficacy also for a given task’s performance via online evaluation of the underlying instantaneous networks before, during, and after the task. Here we provide an updated summary on the connectome analysis for the prediction of performance via the study of task-related dynamics of brain network organization from EEG signals.

  • The Expanding Clinical Universe of Polyglutamine Disease
    Neuroscientist (IF 7.461) Pub Date : 2019-01-07
    Shanshan Huang; Suiqiang Zhu; Xiao-Jiang Li; Shihua Li

    Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of unstable polyQ repeats in their associated disease proteins. To date, the pathogenesis of each disease remains poorly understood, and there are no effective treatments. Growing evidence has indicated that, in addition to neurodegeneration, polyQ-expanded proteins can cause a wide array of abnormalities in peripheral tissues. Indeed, polyQ-expanded proteins are ubiquitously expressed throughout the body and can affect the function of both the central nervous system (CNS) and peripheral tissues. The peripheral effects of polyQ disease proteins include muscle wasting and reduced muscle strength in patients or animal models of spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia type 17 (SCA17). Since skeletal muscle pathology can reflect disease progression and is more accessible for treatment than neurodegeneration in the CNS, understanding how polyQ disease proteins affect skeletal muscle will help elucidate disease mechanisms and the development of new therapeutics. In this review, we focus on important findings in terms of skeletal muscle pathology in polyQ diseases and also discuss the potential mechanisms underlying the major peripheral effects of polyQ disease proteins, as well as their therapeutic implications.

  • Oligodendrocyte Bioenergetics in Health and Disease
    Neuroscientist (IF 7.461) Pub Date : 2018-08-20
    Lauren Rosko; Victoria N. Smith; Reiji Yamazaki; Jeffrey K. Huang

    The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person’s total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.

  • TGFβ1: Friend or Foe During Recovery in Encephalopathy
    Neuroscientist (IF 7.461) Pub Date : 2018-08-17
    Brian H. Kim; Steven W. Levison

    The cytokine transforming growth factor (TGF)-β1 is highly induced after encephalopathic brain injury, with data showing that it can both contribute to the pathophysiology and aid in disease resolution. In the immature brain, sustained TGFβ-signaling after injury may prolong inflammation to both exacerbate acute stage damage and perturb the normal course of development. Yet in adult encephalopathy, elevated TGFβ1 may promote a reparative state. In this review, we highlight the context-dependent actions of TGFβ-signaling in the brain during resolution of encephalopathy and focus on neuronal survival mechanisms that are affected by TGFβ1. We discuss the mechanisms that contribute to the disparate actions of TGFβ1 toward elucidating the long-term neurological and neuropsychiatric consequences that follow encephalopathic injury.

  • Amyloid Plaques of Alzheimer’s Disease as Hotspots of Glutamatergic Activity
    Neuroscientist (IF 7.461) Pub Date : 2018-07-27
    Saak V. Ovsepian; Valerie B. O’Leary; Laszlo Zaborszky; Vasilis Ntziachristos; J. Oliver Dolly

    Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer’s disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer’s disease.

  • New Insights into the Neurobiology of Restless Legs Syndrome
    Neuroscientist (IF 7.461) Pub Date : 2018-07-26
    Sergi Ferré; Diego García-Borreguero; Richard P. Allen; Christopher J. Earley

    Restless legs syndrome (RLS) is a common sensorimotor disorder, whose basic components include a sensory experience, akathisia, and a sleep-related motor sign, periodic leg movements during sleep (PLMS), both associated with an enhancement of the individual’s arousal state. The present review attempts to integrate the major clinical and experimental neurobiological findings into a heuristic pathogenetic model. The model also integrates the recent findings on RLS genetics indicating that RLS has aspects of a genetically moderated neurodevelopmental disorder involving mainly the cortico-striatal-thalamic-cortical circuits. Brain iron deficiency (BID) remains the key initial pathobiological factor and relates to alterations of iron acquisition by the brain, also moderated by genetic factors. Experimental evidence indicates that BID leads to a hyperdopaminergic and hyperglutamatergic states that determine the dysfunction of cortico-striatal-thalamic-cortical circuits in genetically vulnerable individuals. However, the enhanced arousal mechanisms critical to RLS are better explained by functional changes of the ascending arousal systems. Recent experimental and clinical studies suggest that a BID-induced hypoadenosinergic state provides the link for a putative unified pathophysiological mechanism for sensorimotor signs of RLS and the enhanced arousal state.

  • The National Undergraduate Neuroanatomy Competition: Lessons Learned from Partnering with Students to Innovate Undergraduate Neuroanatomy Education
    Neuroscientist (IF 7.461) Pub Date : 2018-07-21
    Kate Geoghegan; December R. Payne; Matthew A. Myers; Samuel Hall; Ahmad Elmansouri; William J. C. Parton; Charlotte H. Harrison; Jonny Stephens; Rob Parker; Shivani Rae; Wassim Merzougui; Eva Nagy; Prarthana Venkatesh; Rachel Parrott; Scott Border

    Undergraduates often perceive neuroscience to be a challenging discipline. As the scope of neuroscience continues to expand, it is important to provide undergraduates with sufficient opportunities to develop their knowledge and skills with the aim of encouraging the future generation of basic and clinical neuroscientists. Through our experience of developing the National Undergraduate Neuroanatomy Competition (NUNC), we have accrued an extensive volume of performance data and subjective insight into the delivery of undergraduate neuroanatomy education, which has the potential to inform how to better engage students within this field. More broadly, our group has implemented a technology enhanced learning platform alongside a peer-assisted teaching program. These achieve the dual purpose of compensating for the reduction in dedicated neuroanatomy teaching hours and encouraging undergraduates to develop an interest in the neurosciences. Here, we consider how improving the learning experience at an undergraduate level encourages further engagement in the neurosciences and the importance of this within the wider neuroscience community.

  • Intracellular Ca2+ Release and Synaptic Plasticity: A Tale of Many Stores
    Neuroscientist (IF 7.461) Pub Date : 2018-07-17
    Zahid Padamsey; William J. Foster; Nigel J. Emptage

    Ca2+ is an essential trigger for most forms of synaptic plasticity. Ca2+ signaling occurs not only by Ca2+ entry via plasma membrane channels but also via Ca2+ signals generated by intracellular organelles. These organelles, by dynamically regulating the spatial and temporal extent of Ca2+ elevations within neurons, play a pivotal role in determining the downstream consequences of neural signaling on synaptic function. Here, we review the role of three major intracellular stores: the endoplasmic reticulum, mitochondria, and acidic Ca2+ stores, such as lysosomes, in neuronal Ca2+ signaling and plasticity. We provide a comprehensive account of how Ca2+ release from these stores regulates short- and long-term plasticity at the pre- and postsynaptic terminals of central synapses.

  • Emotions and the Right Hemisphere: Can New Data Clarify Old Models?
    Neuroscientist (IF 7.461) Pub Date : 2018-07-09
    Guido Gainotti

    Models advanced to explain hemispheric asymmetries in representation of emotions will be discussed following their historical progression. First, the clinical observations that have suggested a general dominance of the right hemisphere for all kinds of emotions will be reviewed. Then the experimental investigations that have led to proposal of a different hemispheric specialization for positive versus negative emotions (valence hypothesis) or, alternatively, for approach versus avoidance tendencies (motivational hypothesis) will be surveyed. The discussion of these general models will be followed by a review of recent studies which have documented laterality effects within specific brain structures, known to play a critical role in different components of emotions, namely the amygdata in the computation of emotionally laden stimuli, the ventromedial prefrontal cortex in the integration between cognition and emotion and in the control of impulsive reactions and the anterior insula in the conscious experience of emotion. Results of these recent investigations support and provide an updated integrated version of early models assuming a general right hemisphere dominance for all kinds of emotions.

  • Purkinje Cell Representations of Behavior: Diary of a Busy Neuron
    Neuroscientist (IF 7.461) Pub Date : 2018-07-09
    Laurentiu S. Popa; Martha L. Streng; Timothy J. Ebner

    Fundamental for understanding cerebellar function is determining the representations in Purkinje cell activity, the sole output of the cerebellar cortex. Up to the present, the most accurate descriptions of the information encoded by Purkinje cells were obtained in the context of motor behavior and reveal a high degree of heterogeneity of kinematic and performance error signals encoded. The most productive framework for organizing Purkinje cell firing representations is provided by the forward internal model hypothesis. Direct tests of this hypothesis show that individual Purkinje cells encode two different forward models simultaneously, one for effector kinematics and one for task performance. Newer results demonstrate that the timing of simple spike encoding of motor parameters spans an extend interval of up to ±2 seconds. Furthermore, complex spike discharge is not limited to signaling errors, can be predictive, and dynamically controls the information in the simple spike firing to meet the demands of upcoming behavior. These rich, diverse, and changing representations highlight the integrative aspects of cerebellar function and offer the opportunity to generalize the cerebellar computational framework over both motor and non-motor domains.

  • Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation
    Neuroscientist (IF 7.461) Pub Date : 2018-06-22
    Mithilesh Kumar Jha; Myungjin Jo; Jae-Hong Kim; Kyoungho Suk

    Microglia-astrocyte crosstalk has recently been at the forefront of glial research. Emerging evidence illustrates that microglia- and astrocyte-derived signals are the functional determinants for the fates of astrocytes and microglia, respectively. By releasing diverse signaling molecules, both microglia and astrocytes establish autocrine feedback and their bidirectional conversation for a tight reciprocal modulation during central nervous system (CNS) insult or injury. Microglia, the constant sensors of changes in the CNS microenvironment and restorers of tissue homeostasis, not only serve as the primary immune cells of the CNS but also regulate the innate immune functions of astrocytes. Similarly, microglia determine the functions of reactive astrocytes, ranging from neuroprotective to neurotoxic. Conversely, astrocytes through their secreted molecules regulate microglial phenotypes and functions ranging from motility to phagocytosis. Altogether, the microglia-astrocyte crosstalk is fundamental to neuronal functions and dysfunctions. This review discusses the current understanding of the intimate molecular conversation between microglia and astrocytes and outlines its potential implications in CNS health and disease.

  • Ammon’s Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration
    Neuroscientist (IF 7.461) Pub Date : 2018-06-05
    Cindy Chi-Ching Pang; Clemens Kiecker; John T. O’Brien; Wendy Noble; Raymond Chuen-Chung Chang

    The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon’s horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.

  • Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and Cerebrospinal Fluid Circulation in the Brain
    Neuroscientist (IF 7.461) Pub Date : 2018-05-25
    Tsutomu Nakada; Ingrid L. Kwee

    The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of brain fluid dynamics. The brain is protected by barriers preventing free access of systemic fluid. The same barrier system, however, also isolates brain interstitial fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic interstitial fluid circulation, cannot be propagated to the interstitial fluid compartment of the brain. Without a proper alternative mechanism, brain interstitial fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate interstitial fluid motion. Interstitial flow in peri-arterial VRS constitutes an essential part of the clearance system for β-amyloid, whereas interstitial flow in peri-venous VRS creates bulk interstitial fluid flow, which, together with the choroid plexus, creates the necessary ventricular cerebrospinal fluid (CSF) volume for proper CSF circulation.

  • Human Stem Cell–Derived Models: Lessons for Autoimmune Diseases of the Nervous System
    Neuroscientist (IF 7.461) Pub Date : 2018-05-20
    Oliver Harschnitz

    Autoimmunity of the peripheral and central nervous system is an important cause of disease and long-term neurological disability. Autoantibodies can target both intracellular and extracellular neuronal epitopes. Autoantibodies that target cell-surface epitopes infer pathogenicity through several distinct mechanisms, while patients often respond to immunotherapy. However, the underlying pathogenesis of these autoantibodies is yet to be fully understood. Human stem cell–based disease modeling, and the rise of induced pluripotent stem cell technology in particular, has revolutionized the fields of disease modeling and therapeutic screening for neurological disorders. These human disease models offer a unique platform in which to study autoimmunity of the nervous system. Here, we take an in-depth look at the possibilities that these models provide to study neuronal autoantibodies and their underlying pathogenesis.

  • Brain-Machine Interfaces: Powerful Tools for Clinical Treatment and Neuroscientific Investigations
    Neuroscientist (IF 7.461) Pub Date : 2018-05-17
    Marc W. Slutzky

    Brain-machine interfaces (BMIs) have exploded in popularity in the past decade. BMIs, also called brain-computer interfaces, provide a direct link between the brain and a computer, usually to control an external device. BMIs have a wide array of potential clinical applications, ranging from restoring communication to people unable to speak due to amyotrophic lateral sclerosis or a stroke, to restoring movement to people with paralysis from spinal cord injury or motor neuron disease, to restoring memory to people with cognitive impairment. Because BMIs are controlled directly by the activity of prespecified neurons or cortical areas, they also provide a powerful paradigm with which to investigate fundamental questions about brain physiology, including neuronal behavior, learning, and the role of oscillations. This article reviews the clinical and neuroscientific applications of BMIs, with a primary focus on motor BMIs.

  • Mitochondrial Zn2+ Accumulation: A Potential Trigger of Hippocampal Ischemic Injury
    Neuroscientist (IF 7.461) Pub Date : 2018-05-10
    Sung G. Ji; Yuliya V. Medvedeva; Hwai-Lee Wang; Hong Z. Yin; John H. Weiss

    Ischemic stroke is a major cause of death and disabilities worldwide, and it has been long hoped that improved understanding of relevant injury mechanisms would yield targeted neuroprotective therapies. While Ca2+ overload during ischemia-induced glutamate excitotoxicity has been identified as a major contributor, failures of glutamate targeted therapies to achieve desired clinical efficacy have dampened early hopes for the development of new treatments. However, additional studies examining possible contributions of Zn2+, a highly prevalent cation in the brain, have provided new insights that may help to rekindle the enthusiasm. In this review, we discuss both old and new findings yielding clues as to sources of the Zn2+ that accumulates in many forebrain neurons after ischemia, and mechanisms through which it mediates injury. Specifically, we highlight the growing evidence of important Zn2+ effects on mitochondria in promoting neuronal injury. A key focus has been to examine Zn2+ contributions to the degeneration of highly susceptible hippocampal pyramidal neurons. Recent studies provide evidence of differences in sources of Zn2+ and its interactions with mitochondria in CA1 versus CA3 neurons that may pertain to their differential vulnerabilities in disease. We propose that Zn2+-induced mitochondrial dysfunction is a critical and potentially targetable early event in the ischemic neuronal injury cascade, providing opportunities for the development of novel neuroprotective strategies to be delivered after transient ischemia.

  • Scientists, Instruments, and Even Brains in Transfer: German-Spanish Postwar Networks and the Construction of the Neuroendocrine System (1952-1960)
    Neuroscientist (IF 7.461) Pub Date : 2018-01-17
    Raúl Velasco Morgado

    This article presents the process of relocation of hegemonies and “center-periphery” dynamics in neuroanatomy after World War II through the study of the links between the Spanish anatomical school of José Escolar García and some German institutions. We have analyzed their works on the morphology of the neuroendocrine system as a case study, showing how the first contacts of the Spaniards with the United States started a material transfer process between centers on both sides of the Atlantic Ocean through the mediation—and adaptation—of the periphery. The case also shows how scientific networks in the “new” Europe were reestablished after the Nazi era and how important these systems were for the transfer of knowledge, using them for the circulation of experts, instruments, and even biological samples.

  • Dysregulation of Transcription Factors: A Key Culprit Behind Neurodegenerative Disorders
    Neuroscientist (IF 7.461) Pub Date : 2018-11-28
    Wei Jin; Talal Jamil Qazi; Zhenzhen Quan; Nuomin Li; Hong Qing

    Neurodegenerative diseases (NDs) are considered heterogeneous disorders characterized by progressive pathological changes in neuronal systems. Transcription factors are protein molecules that are important in regulating the expression of genes. Although the clinical manifestations of NDs vary, the pathological processes appear similar with regard to neuroinflammation, oxidative stress, and proteostasis, to which, as numerous studies have discovered, transcription factors are closely linked. In this review, we summarized and reviewed the roles of transcription factors in NDs, and then we elucidated their functions during pathological processes, and finally we discussed their therapeutic values in NDs.

  • ER Stress, CREB, and Memory: A Tangled Emerging Link in Disease
    Neuroscientist (IF 7.461) Pub Date : 2018-11-26
    Nilkantha Sen

    The brain undergoes several changes at structural, molecular, and cellular levels leading to alteration in its functions and these processes are primarily maintained by proteostasis in cells. However, an imbalance in proteostasis due to the abnormal accumulation of protein aggregates induces endoplasmic reticulum (ER) stress. This event, in turn, activate the unfolded protein response; however, in most neurodegenerative conditions and brain injury, an uncontrolled unfolded protein response elicits memory dysfunction. Although the underlying signaling mechanism for impairment of memory function following induction of ER stress remains elusive, recent studies have highlighted that inactivation of a transcription factor, CREB, which is essential for synaptic function and memory formation, plays an essential role for ER stress–induced synaptic and memory dysfunction. In this review, current studies and most updated view on how ER stress affects memory function in both physiological and pathological conditions will be highlighted.

  • Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity
    Neuroscientist (IF 7.461) Pub Date : 2018-11-17
    Colm Cunningham; Aisling Dunne; Ana Belen Lopez-Rodriguez

    Astrocytes are the most numerous cell type in the brain and perform several essential functions in supporting neuronal metabolism and actively participating in neural circuit and behavioral function. They also have essential roles as innate immune cells in responding to local neuropathology, and the manner in which they respond to brain injury and degeneration is the subject of increasing attention in neuroscience. Although activated astrocytes have long been thought of as a relatively homogenous population, which alter their phenotype in a relatively stereotyped way upon central nervous system injury, the last decade has revealed substantial heterogeneity in the basal state and significant heterogeneity of phenotype during reactive astrocytosis. Thus, phenotypic diversity occurs at two distinct levels: that determined by regionality and development and that determined by temporally dynamic changes to the environment of astrocytes during pathology. These inflammatory and pathological states shape the phenotype of these cells, with different consequences for destruction or recovery of the local tissue, and thus elucidating these phenotypic changes has significant therapeutic implications. In this review, we will focus on the phenotypic heterogeneity of astrocytes in health and disease and their propensity to change that phenotype upon subsequent stimuli.

  • Are We “Motorically” Wired to Others? High-Level Motor Computations and Their Role in Autism
    Neuroscientist (IF 7.461) Pub Date : 2017-12-22
    Luca Casartelli; Alessandra Federici; Emilia Biffi; Massimo Molteni; Luca Ronconi

    High-level motor computations reflect abstract components far apart from the mere motor performance. Neural correlates of these computations have been explored both in nonhuman and human primates, supporting the idea that our brain recruits complex nodes for motor representations. Of note, these computations have exciting implications for social cognition, and they also entail important challenges in the context of autism. Here, we focus on these challenges benefiting from recent studies addressing motor interference, motor resonance, and high-level motor planning. In addition, we suggest new ideas about how one maps and shares the (motor) space with others. Taken together, these issues inspire intriguing and fascinating questions about the social tendency of our high-level motor computations, and this tendency may indicate that we are “motorically” wired to others. Thus, after furnishing preliminary insights on putative neural nodes involved in these computations, we focus on how the hypothesized social nature of high-level motor computations may be anomalous or limited in autism, and why this represents a critical challenge for the future.

  • Orientation Encoding and Viewpoint Invariance in Face Recognition: Inferring Neural Properties from Large-Scale Signals
    Neuroscientist (IF 7.461) Pub Date : 2018-06-01
    Fernando M. Ramírez

    Viewpoint-invariant face recognition is thought to be subserved by a distributed network of occipitotemporal face-selective areas that, except for the human anterior temporal lobe, have been shown to also contain face-orientation information. This review begins by highlighting the importance of bilateral symmetry for viewpoint-invariant recognition and face-orientation perception. Then, monkey electrophysiological evidence is surveyed describing key tuning properties of face-selective neurons—including neurons bimodally tuned to mirror-symmetric face-views—followed by studies combining functional magnetic resonance imaging (fMRI) and multivariate pattern analyses to probe the representation of face-orientation and identity information in humans. Altogether, neuroimaging studies suggest that face-identity is gradually disentangled from face-orientation information along the ventral visual processing stream. The evidence seems to diverge, however, regarding the prevalent form of tuning of neural populations in human face-selective areas. In this context, caveats possibly leading to erroneous inferences regarding mirror-symmetric coding are exposed, including the need to distinguish angular from Euclidean distances when interpreting multivariate pattern analyses. On this basis, this review argues that evidence from the fusiform face area is best explained by a view-sensitive code reflecting head angular disparity, consistent with a role of this area in face-orientation perception. Finally, the importance is stressed of explicit models relating neural properties to large-scale signals.

  • Neural Oscillations Orchestrate Multisensory Processing
    Neuroscientist (IF 7.461) Pub Date : 2018-02-09
    Julian Keil; Daniel Senkowski

    At any given moment, we receive input through our different sensory systems, and this information needs to be processed and integrated. Multisensory processing requires the coordinated activity of distinct cortical areas. Key mechanisms implicated in these processes include local neural oscillations and functional connectivity between distant cortical areas. Evidence is now emerging that neural oscillations in distinct frequency bands reflect different mechanisms of multisensory processing. Moreover, studies suggest that aberrant neural oscillations contribute to multisensory processing deficits in clinical populations, such as schizophrenia. In this article, we review recent literature on the neural mechanisms underlying multisensory processing, focusing on neural oscillations. We derive a framework that summarizes findings on (1) stimulus-driven multisensory processing, (2) the influence of top-down information on multisensory processing, and (3) the role of predictions for the formation of multisensory perception. We propose that different frequency band oscillations subserve complementary mechanisms of multisensory processing. These processes can act in parallel and are essential for multisensory processing.

  • Epigenetic Control of Schwann Cells
    Neuroscientist (IF 7.461) Pub Date : 2018-01-07
    Ki H. Ma; John Svaren

    The journey of Schwann cells from their origin in the neural crest to their ensheathment and myelination of peripheral nerves is a remarkable one. Their apparent static function in enabling saltatory conduction of mature nerve is not only vital for long-term health of peripheral nerve but also belies an innate capacity of terminally differentiated Schwann cells to radically alter their differentiation status in the face of nerve injury. The transition from migrating neural crest cells to nerve ensheathment, and then myelination of large diameter axons has been characterized extensively and several of the transcriptional networks have been identified. However, transcription factors must also modify chromatin structure during Schwann cell maturation and this review will focus on chromatin modification machinery that is involved in promoting the transition to, and maintenance of, myelinating Schwann cells. In addition, Schwann cells are known to play important regenerative roles after peripheral nerve injury, and information on epigenomic reprogramming of the Schwann cell genome has emerged. Characterization of epigenomic requirements for myelin maintenance and Schwann cell responses to injury will be vital in understanding how the various Schwann cell functions can be optimized to maintain and repair peripheral nerve function.

  • The Ubiquitin-Proteasome System and Memory: Moving Beyond Protein Degradation
    Neuroscientist (IF 7.461) Pub Date : 2018-03-12
    Timothy J. Jarome; Rishi K. Devulapalli

    Cellular models of memory formation have focused on the need for protein synthesis. Recently, evidence has emerged that protein degradation mediated by the ubiquitin-proteasome system (UPS) is also important for this process. This has led to revised cellular models of memory formation that focus on a balance between protein degradation and synthesis. However, protein degradation is only one function of the UPS. Studies using single-celled organisms have shown that non-proteolytic ubiquitin-proteasome signaling is involved in histone modifications and DNA methylation, suggesting that ubiquitin and the proteasome can regulate chromatin remodeling independent of protein degradation. Despite this evidence, the idea that the UPS is more than a protein degradation pathway has not been examined in the context of memory formation. In this article, we summarize recent findings implicating protein degradation in memory formation and discuss various ways in which both ubiquitin signaling and the proteasome could act independently to regulate epigenetic-mediated transcriptional processes necessary for learning-dependent synaptic plasticity. We conclude by proposing comprehensive models of how non-proteolytic functions of the UPS could work in concert to control epigenetic regulation of the cellular memory consolidation process, which will serve as a framework for future studies examining the role of the UPS in memory formation.

  • Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons
    Neuroscientist (IF 7.461) Pub Date : 2018-02-28
    Emily L. Dennis; Talin Babikian; Christopher C. Giza; Paul M. Thompson; Robert F. Asarnow

    Traumatic brain injury (TBI) is a significant public health problem in the United States, especially for children and adolescents. Current epidemiological data estimate over 600,000 patients younger than 20 years are treated for TBI in emergency rooms annually. While many patients experience a full recovery, for others there can be long-lasting cognitive, neurological, psychological, and behavioral disruptions. TBI in youth can disrupt ongoing brain development and create added family stress during a formative period. The neuroimaging methods used to assess brain injury improve each year, providing researchers a more detailed characterization of the injury and recovery process. In this review, we cover current imaging methods used to quantify brain disruption post-injury, including structural magnetic resonance imaging (MRI), diffusion MRI, functional MRI, resting state fMRI, and magnetic resonance spectroscopy (MRS), with brief coverage of other methods, including electroencephalography (EEG), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). We include studies focusing on pediatric moderate-severe TBI from 2 months post-injury and beyond. While the morbidity of pediatric TBI is considerable, continuing advances in imaging methods have the potential to identify new treatment targets that can lead to significant improvements in outcome.

  • Low Back Pain: The Potential Contribution of Supraspinal Motor Control and Proprioception
    Neuroscientist (IF 7.461) Pub Date : 2018-11-02
    Michael Lukas Meier; Andrea Vrana; Petra Schweinhardt

    Motor control, which relies on constant communication between motor and sensory systems, is crucial for spine posture, stability and movement. Adaptions of motor control occur in low back pain (LBP) while different motor adaption strategies exist across individuals, probably to reduce LBP and risk of injury. However, in some individuals with LBP, adapted motor control strategies might have long-term consequences, such as increased spinal loading that has been linked with degeneration of intervertebral discs and other tissues, potentially maintaining recurrent or chronic LBP. Factors contributing to motor control adaptations in LBP have been extensively studied on the motor output side, but less attention has been paid to changes in sensory input, specifically proprioception. Furthermore, motor cortex reorganization has been linked with chronic and recurrent LBP, but underlying factors are poorly understood. Here, we review current research on behavioral and neural effects of motor control adaptions in LBP. We conclude that back pain-induced disrupted or reduced proprioceptive signaling likely plays a pivotal role in driving long-term changes in the top-down control of the motor system via motor and sensory cortical reorganization. In the outlook of this review, we explore whether motor control adaptations are also important for other (musculoskeletal) pain conditions.

  • Brain-Derived Neurotrophic Factor (BDNF): Novel Insights into Regulation and Genetic Variation
    Neuroscientist (IF 7.461) Pub Date : 2018-11-02
    Michael Notaras; Maarten van den Buuse

    Since its discovery, brain-derived neurotrophic factor (BDNF) has spawned a literature that now spans 35 years of research. While all neurotrophins share considerable overlap in sequence homology and their processing, BDNF has become the most widely studied neurotrophin because of its broad roles in brain homeostasis, health, and disease. Although research on BDNF has produced thousands of articles, there remain numerous long-standing questions on aspects of BDNF molecular biology and signaling. Here we provide a comprehensive review, including both a historical narrative and a forward-looking perspective on advances in the actions of BDNF within the brain. We specifically review BDNF’s gene structure, peptide composition (including domains, posttranslational modifications and putative motif sites), mechanisms of transport, signaling pathway recruitment, and other recent developments including the functional effects of genetic variation and the discovery of a new BDNF prodomain ligand. This body of knowledge illustrates a highly conserved and complex role for BDNF within the brain, that promotes the idea that the neurotrophin biology of BDNF is diverse and that any disease involvement is likely to be equally multifarious.

  • Thinking Outside the Box (and Arrow): Current Themes in Striatal Dysfunction in Movement Disorders
    Neuroscientist (IF 7.461) Pub Date : 2018-10-31
    Joshua L. Plotkin; Joshua A. Goldberg

    The basal ganglia are an intricately connected assembly of subcortical nuclei, forming the core of an adaptive network connecting cortical and thalamic circuits. For nearly three decades, researchers and medical practitioners have conceptualized how the basal ganglia circuit works, and how its pathology underlies motor disorders such as Parkinson’s and Huntington’s diseases, using what is often referred to as the “box-and-arrow model”: a circuit diagram showing the broad strokes of basal ganglia connectivity and the pathological increases and decreases in the weights of specific connections that occur in disease. While this model still has great utility and has led to groundbreaking strategies to treat motor disorders, our evolving knowledge of basal ganglia function has made it clear that this classic model has several shortcomings that severely limit its predictive and descriptive abilities. In this review, we will focus on the striatum, the main input nucleus of the basal ganglia. We describe recent advances in our understanding of the rich microcircuitry and plastic capabilities of the striatum, factors not captured by the original box-and-arrow model, and provide examples of how such advances inform our current understanding of the circuit pathologies underlying motor disorders.

  • GABAergic Interneurons in Seizures: Investigating Causality With Optogenetics
    Neuroscientist (IF 7.461) Pub Date : 2018-10-15
    Vincent Magloire; Marion S. Mercier; Dimitri M. Kullmann; Ivan Pavlov

    Seizures are complex pathological network events characterized by excessive and hypersynchronized activity of neurons, including a highly diverse population of GABAergic interneurons. Although the primary function of inhibitory interneurons under normal conditions is to restrain excitation in the brain, this system appears to fail intermittently, allowing runaway excitation. Recent developments in optogenetics, combined with genetic tools and advanced electrophysiological and imaging techniques, allow us for the first time to assess the causal roles of identified cell-types in network dynamics. While these methods have greatly increased our understanding of cortical microcircuits in epilepsy, the roles played by individual GABAergic cell-types in controlling ictogenesis remain incompletely resolved. Indeed, the ability of interneurons to suppress epileptic discharges varies across different subtypes, and an accumulating body of evidence paradoxically implicates some interneuron subtypes in the initiation and maintenance of epileptiform activity. Here, we bring together findings from this growing field and discuss what can be inferred regarding the causal role of different GABAergic cell-types in seizures.

  • Twitches, Blinks, and Fidgets: Important Generators of Ongoing Neural Activity
    Neuroscientist (IF 7.461) Pub Date : 2018-10-12
    Patrick J. Drew; Aaron T. Winder; Qingguang Zhang

    Animals and humans continuously engage in small, spontaneous motor actions, such as blinking, whisking, and postural adjustments (“fidgeting”). These movements are accompanied by changes in neural activity in sensory and motor regions of the brain. The frequency of these motions varies in time, is affected by sensory stimuli, arousal levels, and pathology. These fidgeting behaviors can be entrained by sensory stimuli. Fidgeting behaviors will cause distributed, bilateral functional activation in the 0.01 to 0.1 Hz frequency range that will show up in functional magnetic resonance imaging and wide-field calcium neuroimaging studies, and will contribute to the observed functional connectivity among brain regions. However, despite the large potential of these behaviors to drive brain-wide activity, these fidget-like behaviors are rarely monitored. We argue that studies of spontaneous and evoked brain dynamics in awake animals and humans should closely monitor these fidgeting behaviors. Differences in these fidgeting behaviors due to arousal or pathology will “contaminate” ongoing neural activity, and lead to apparent differences in functional connectivity. Monitoring and accounting for the brain-wide activations by these behaviors is essential during experiments to differentiate fidget-driven activity from internally driven neural dynamics.

  • Region-Specific Phenotypes of Microglia: The Role of Local Regulatory Cues
    Neuroscientist (IF 7.461) Pub Date : 2018-10-03
    Lindsay M. De Biase; Antonello Bonci

    Microglia are ubiquitous, macrophage like cells within the central nervous system (CNS) that play critical roles in supporting neuronal health and viability. They can also influence neuronal membrane properties and synaptic connectivity, positioning microglia as key cellular players in both physiological and pathological contexts. Microglia have generally been assumed to be equivalent throughout the CNS, but accumulating evidence indicates that their properties vary substantially across distinct CNS regions. In comparison to our understanding of neuronal diversity and its functional importance, our knowledge about causes and consequences of microglial regional heterogeneity is extremely limited. To fully understand how microglia influence the function of specific neuronal populations and shape heightened susceptibility of some neurons to damage and disease, greater focus on microglial heterogeneity is needed.

  • Functional and Neuroanatomical Bases of Developmental Stuttering: Current Insights
    Neuroscientist (IF 7.461) Pub Date : 2018-09-28
    Soo-Eun Chang; Emily O. Garnett; Andrew Etchell; Ho Ming Chow

    Affecting 5% of all preschool-aged children and 1% of the general population, developmental stuttering—also called childhood-onset fluency disorder—is a complex, multifactorial neurodevelopmental disorder characterized by frequent disruption of the fluent flow of speech. Over the past two decades, neuroimaging studies of both children and adults who stutter have begun to provide significant insights into the neurobiological bases of stuttering. This review highlights convergent findings from this body of literature with a focus on functional and structural neuroimaging results that are supported by theoretically driven neurocomputational models of speech production. Updated views on possible mechanisms of stuttering onset and persistence, and perspectives on promising areas for future research into the mechanisms of stuttering, are discussed.

  • A Brain on a Roller Coaster: Can the Dopamine Reward System Act as a Protagonist to Subdue the Ups and Downs of Bipolar Disorder?
    Neuroscientist (IF 7.461) Pub Date : 2017-06-14
    Shokouh Arjmand; Mina Behzadi; Gary J. Stephens; Sara Ezzatabadipour; Rostam Seifaddini; Shahrad Arjmand; Mohammad Shabani

    One of the most interesting but tenebrous parts of the bipolar disorder (BD) story is the switch between (hypo)mania and depression, which can give bipolar patients a thrilling, but somewhat perilous, ‘ride’. Numerous studies have pointed out that there are some recognizable differences (either state-dependent or state-independent) in several brain regions of people with BD, including components of the brain’s reward system. Understanding the underpinning mechanisms of high and low mood statuses in BD has potential, not only for the development of highly specific and selective pharmaceutical agents, but also for better treatment approaches and psychological interventions to manage BD and, thus, give patients a safer ride. Herein, we review evidence that supports involvement of the reward system in the pathophysiology of mood swings, with the main focus on the mesocorticolimbic dopaminergic neural circuitry. Principally using findings from neuroimaging studies, we aim to signpost readers as to how mood alterations may affect different areas of the reward system and how antipsychotic drugs can influence the activity of these brain areas. Finally, we critically evaluate the hypothesis that the mesocorticolimbic dopamine reward system may act as a functional rheostat for different mood states.

  • Pericytes Make Spinal Cord Breathless after Injury
    Neuroscientist (IF 7.461) Pub Date : 2017-09-21
    Viviani M. Almeida; Ana E. Paiva; Isadora F. G. Sena; Akiva Mintz; Luiz Alexandre V. Magno; Alexander Birbrair

    Traumatic spinal cord injury is a devastating condition that leads to significant neurological deficits and reduced quality of life. Therapeutic interventions after spinal cord lesions are designed to address multiple aspects of the secondary damage. However, the lack of detailed knowledge about the cellular and molecular changes that occur after spinal cord injury restricts the design of effective treatments. Li and colleagues using a rat model of spinal cord injury and in vivo microscopy reveal that pericytes play a key role in the regulation of capillary tone and blood flow in the spinal cord below the site of the lesion. Strikingly, inhibition of specific proteins expressed by pericytes after spinal cord injury diminished hypoxia and improved motor function and locomotion of the injured rats. This work highlights a novel central cellular population that might be pharmacologically targeted in patients with spinal cord trauma. The emerging knowledge from this research may provide new approaches for the treatment of spinal cord injury.

  • You Can Observe a Lot by Watching: Hughlings Jackson’s Underappreciated and Prescient Ideas about Brain Control of Movement
    Neuroscientist (IF 7.461) Pub Date : 2018-06-14
    Ari Berkowitz

    John Hughlings Jackson, the 19th-century British neurologist, first described what are today called Jacksonian seizures. He is generally associated with somatotopy, the idea that neighboring brain regions control neighboring body parts, as later represented pictorially in Wilder Penfield’s “homunculus,” or little man in the brain. Jackson’s own views, however, were quite different, though this is seldom appreciated. In an 1870 article, Jackson advanced the hypotheses that each region of the cerebrum controls movements of multiple body parts, but to different degrees, and that the “march” of movements that typically occurs during Jacksonian seizures is caused by the downstream connections of the overactive neurons at the seizure focus, rather than a somatotopic organization of the cerebrum. Jackson’s hypotheses, which were based almost entirely on his careful observations of movements during seizures, are well within the range of current hypotheses about how the frontal lobe is organized to control movements and thus deserve renewed attention.

  • Versatility and Flexibility of Cortical Circuits
    Neuroscientist (IF 7.461) Pub Date : 2017-09-21
    Melissa S. Haley; Arianna Maffei

    Cortical circuits are known to be plastic and adaptable, as shown by an impressive body of evidence demonstrating the ability of cortical circuits to adapt to changes in environmental stimuli, development, learning, and insults. In this review, we will discuss some of the features of cortical circuits that are thought to facilitate cortical circuit versatility and flexibility. Throughout life, cortical circuits can be extensively shaped and refined by experience while preserving their overall organization, suggesting that mechanisms are in place to favor change but also to stabilize some aspects of the circuit. First, we will describe the basic organization and some of the common features of cortical circuits. We will then discuss how this underlying cortical structure provides a substrate for the experience- and learning-dependent processes that contribute to cortical flexibility.

  • Epigenome Interactions with Patterned Neuronal Activity
    Neuroscientist (IF 7.461) Pub Date : 2018-02-27
    Jillian Belgrad; R. Douglas Fields

    The temporal coding of action potential activity is fundamental to nervous system function. Here we consider how gene expression in neurons is regulated by specific patterns of action potential firing, with an emphasis on new information on epigenetic regulation of gene expression. Patterned action potential activity activates intracellular signaling networks selectively in accordance with the kinetics of activation and inactivation of second messengers, phosphorylation and dephosphorylation of protein kinases, and cytoplasmic and nuclear calcium dynamics, which differentially activate specific transcription factors. Increasing evidence also implicates activity-dependent regulation of epigenetic mechanisms to alter chromatin architecture. Changes in three-dimensional chromatin structure, including chromatin compaction, looping, double-stranded DNA breaks, histone and DNA modification, are altered by action potential activity to selectively inhibit or promote transcription of specific genes. These mechanisms of activity-dependent regulation of gene expression are important in neural development, plasticity, and in neurological and psychological disorders.

  • LRRK2 Phosphorylation: Behind the Scenes
    Neuroscientist (IF 7.461) Pub Date : 2018-01-31
    Tina De Wit; Veerle Baekelandt; Evy Lobbestael

    Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are known today as the most common genetic cause of Parkinson’s disease (PD). LRRK2 is a large protein that is hypothesized to regulate other proteins as a scaffold in downstream signaling pathways. This is supported by the multiple domain composition of LRRK2 with several protein-protein interaction domains combined with kinase and GTPase activity. LRRK2 is highly phosphorylated at sites that are strictly controlled by upstream regulators, including its own kinase domain. In cultured cells, most pathogenic mutants display increased autophosphorylation at S1292, but decreased phosphorylation at sites controlled by other kinases. We only begin to understand how LRRK2 phosphorylation is regulated and how this impacts its physiological and pathological function. Intriguingly, LRRK2 kinase inhibition, currently one of the most prevailing disease-modifying therapeutic strategies for PD, induces LRRK2 dephosphorylation at sites that are also dephosphorylated in pathogenic variants. In addition, LRRK2 kinase inhibition can induce LRRK2 protein degradation, which might be related to the observed inhibitor-induced adverse effects on the lung in rodents and non-human primates, as it resembles the lung pathology in LRRK2 knock-out animals. In this review, we will provide an overview of how LRRK2 phosphorylation is regulated and how this complex regulation relates to several molecular and cellular features of LRRK2.

  • GABA—from Inhibition to Cognition: Emerging Concepts
    Neuroscientist (IF 7.461) Pub Date : 2017-10-12
    T. Schmidt-Wilcke; E. Fuchs; K. Funke; A. Vlachos; F. Müller-Dahlhaus; N. A. J. Puts; R. E. Harris; R. A. E. Edden

    Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

  • Aging in the Brain: New Roles of Epigenetics in Cognitive Decline
    Neuroscientist (IF 7.461) Pub Date : 2018-06-07
    Jolie D. Barter; Thomas C. Foster

    Gene expression in the aging brain depends on transcription signals generated by senescent physiology, interacting with genetic and epigenetic programs. In turn, environmental factors influence epigenetic mechanisms, such that an epigenetic–environmental link may contribute to the accumulation of cellular damage, susceptibility or resilience to stressors, and variability in the trajectory of age-related cognitive decline. Epigenetic mechanisms, DNA methylation and histone modifications, alter chromatin structure and the accessibility of DNA. Furthermore, small non-coding RNA, termed microRNA (miRNA) bind to messenger RNA (mRNA) to regulate translation. In this review, we examine key questions concerning epigenetic mechanisms in regulating the expression of genes associated with brain aging and age-related cognitive decline. In addition, we highlight the interaction of epigenetics with senescent physiology and environmental factors in regulating transcription.

  • Behavioral Manipulation by Optogenetics in the Nonhuman Primate
    Neuroscientist (IF 7.461) Pub Date : 2017-09-05
    Chunshan Deng; Hong Yuan; Ji Dai

    Given their neuroanatomical similarities to humans and their ability to perform complex behaviors, the nonhuman primate has been an important model for understanding complex systems such as sensory processing, motor control, social interaction, and nervous system disorders. Optogenetics offers cell-type specific neural control with millisecond precision, making it a powerful neural modulation technique. Combining optogenetics with the nonhuman primate model promises to lead to significant advances in both basic and applied research. In the past few years, optogenetics has made considerable progress in the nonhuman primate. Here, we systematically review the current state-of-art of optogenetics in the nonhuman primate with an emphasis on behavioral manipulation. Given its recent successes, we believe that the progress in the nonhuman primate will boost the translation of optogenetics to clinical applications in the near future.

  • Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications
    Neuroscientist (IF 7.461) Pub Date : 2018-02-04
    Roberta Balestrino; Anthony H. V. Schapira

    Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset. The molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are multiple and not yet fully elucidated, they include alpha-synuclein aggregation, lysosomal-autophagy dysfunction and endoplasmic reticulum stress. Moreover, dysfunction of glucocerebrosidase has also been demonstrated in non-GBA PD, suggesting its interaction with other pathogenic mechanisms. Therefore, GBA enzyme function represents an interesting pharmacological target for PD. Cell and animal models suggest that increasing GBA enzyme activity can reduce alpha-synuclein levels. Clinical trials of ambroxol, a glucocerebrosidase chaperone, are currently ongoing in PD and PD dementia, as is a trial of substrate reduction therapy. The aim of this review is to summarise the main features of GBA-PD and discuss the implications of glucocerebrosidase modulation on PD pathogenesis.

  • Cellular Origin of [18F]FDG-PET Imaging Signals During Ceftriaxone-Stimulated Glutamate Uptake: Astrocytes and Neurons
    Neuroscientist (IF 7.461) Pub Date : 2017-12-24
    Gerald A. Dienel; Kevin L. Behar; Douglas L. Rothman

    Ceftriaxone stimulates astrocytic uptake of the excitatory neurotransmitter glutamate, and it is used to treat glutamatergic excitotoxicity that becomes manifest during many brain diseases. Ceftriaxone-stimulated glutamate transport was reported to drive signals underlying [18F]fluorodeoxyglucose-positron emission tomographic ([18F]FDG-PET) metabolic images of brain glucose utilization and interpreted as supportive of the notion of lactate shuttling from astrocytes to neurons. This study draws attention to critical roles of astrocytes in the energetics and imaging of brain activity, but the results are provocative because (1) the method does not have cellular resolution or provide information about downstream pathways of glucose metabolism, (2) neuronal and astrocytic [18F]FDG uptake were not separately measured, and (3) strong evidence against lactate shuttling was not discussed. Evaluation of potential metabolic responses to ceftriaxone suggests lack of astrocytic specificity and significant contributions by pre- and postsynaptic neuronal compartments. Indeed, astrocytic glycolysis may not make a strong contribution to the [18F]FDG-PET signal because partial or complete oxidation of one glutamate molecule on its uptake generates enough ATP to fuel uptake of 3 to 10 more glutamate molecules, diminishing reliance on glycolysis. The influence of ceftriaxone on energetics of glutamate-glutamine cycling must be determined in astrocytes and neurons to elucidate its roles in excitotoxicity treatment.

  • Interneuron Cooperativity in Cortical Circuits
    Neuroscientist (IF 7.461) Pub Date : 2017-09-27
    Mahesh M. Karnani; Jesse Jackson

    Neocortical neurons tend to be coactive in groups called ensembles. However, sometimes, individual neurons also spike alone, independent of the ensemble. What processes regulate the transition between individual and cooperative action? Inspired by classical work in biochemistry, we apply the concept of neuronal cooperativity to explore this question. With a focus on neocortical inhibitory interneurons, we offer a working definition of neuronal cooperativity, review its recorded incidences and proposed mechanisms, and describe experimental approaches that will demonstrate and further describe this action. We suggest that cooperativity of “neuron teams” is manifested in vivo through their coactivity, as well as via the action of individual “soloist neurons” in the low end of the sigmoidal cooperativity curve. Finally, we explore the evidence for and implications of individual and team action of neurons.

  • Rethinking the Role of the Angular Gyrus in Remembering the Past and Imagining the Future: The Contextual Integration Model
    Neuroscientist (IF 7.461) Pub Date : 2017-10-10
    Siddharth Ramanan; Olivier Piguet; Muireann Irish

    Despite consistent activation on tasks of episodic memory, the precise contribution of the left angular gyrus (AG) to mnemonic functions remains vigorously debated. Mounting evidence suggests that AG activity scales with subjective ratings of vividness and confidence in recollection, with further evidence pointing to its involvement during construction of detailed and coherent future simulations. Lesion studies, however, indicate that damage to the AG does not render patients amnesic on standard source and associative memory paradigms. To reconcile these findings, we present the Contextual Integration Model as a unifying framework that couches the mnemonic role of the AG in terms of multimodal integration and representation of contextual information across temporal contexts. Irrespective of whether one is remembering the past or constructing future or hypothetical scenarios, the Contextual Integration Model holds that the core elements of an event (i.e., the who, what, when, where) are bound within the medial temporal lobes while the multimodal details, which give rise to perceptually rich recollection, are integrated and represented in the AG. Building on previous work, the Contextual Integration Model therefore provides a comprehensive exposition of the mnemonic and constructive functions of the AG across temporal contexts, offering a novel test-bed for future work.

  • Tinnitus: Prospects for Pharmacological Interventions With a Seesaw Model
    Neuroscientist (IF 7.461) Pub Date : 2017-10-09
    Hannah Tetteh; Minseok Lee; C. Geoffrey Lau; Sunggu Yang; Sungchil Yang

    Chronic tinnitus, the perception of lifelong constant ringing in ear, is one capital cause of disability in modern society. It is often present with various comorbid factors that severely affect quality of life, including insomnia, deficits in attention, anxiety, and depression. Currently, there are limited therapeutic treatments for alleviation of tinnitus. Tinnitus can involve a shift in neuronal excitation/inhibition (E/I) balance, which is largely modulated by ion channels and receptors. Thus, ongoing research is geared toward pharmaceutical approaches that modulate the function of ion channels and receptors. Here, we propose a seesaw model that delineates how tinnitus-related ion channels and receptors are involved in homeostatic E/I balance of neurons. This review provides a thorough account of our current mechanistic understanding of tinnitus and insight into future direction of drug development.

  • Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox
    Neuroscientist (IF 7.461) Pub Date : 2018-03-15
    Zachary Niday; Anastasios V. Tzingounis

    Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

  • Neural Mechanisms of Inflammation-Induced Fever
    Neuroscientist (IF 7.461) Pub Date : 2018-03-20
    Anders Blomqvist; David Engblom

    Fever is a common symptom of infectious and inflammatory disease. It is well-established that prostaglandin E2 is the final mediator of fever, which by binding to its EP3 receptor subtype in the preoptic hypothalamus initiates thermogenesis. Here, we review the different hypotheses on how the presence of peripherally released pyrogenic substances can be signaled to the brain to elicit fever. We conclude that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E2 synthesis in these cells. The evidence for a role for other signaling routes for fever, such as signaling via circumventricular organs and peripheral nerves, as well as transfer into the brain of peripherally synthesized prostaglandin E2 are yet far from conclusive. We also review the efferent limb of the pyrogenic pathways. We conclude that it is well established that prostaglandin E2 binding in the preoptic hypothalamus produces fever by disinhibition of presympathetic neurons in the brain stem, but there is yet little understanding of the mechanisms by which factors such as nutritional status and ambient temperature shape the response to the peripheral immune challenge.

  • Restoring Motor Functions After Stroke: Multiple Approaches and Opportunities
    Neuroscientist (IF 7.461) Pub Date : 2017-11-07
    Estelle Raffin; Friedhelm C. Hummel

    More than 1.5 million people suffer a stroke in Europe per year and more than 70% of stroke survivors experience limited functional recovery of their upper limb, resulting in diminished quality of life. Therefore, interventions to address upper-limb impairment are a priority for stroke survivors and clinicians. While a significant body of evidence supports the use of conventional treatments, such as intensive motor training or constraint-induced movement therapy, the limited and heterogeneous improvements they allow are, for most patients, usually not sufficient to return to full autonomy. Various innovative neurorehabilitation strategies are emerging in order to enhance beneficial plasticity and improve motor recovery. Among them, robotic technologies, brain-computer interfaces, or noninvasive brain stimulation (NIBS) are showing encouraging results. These innovative interventions, such as NIBS, will only provide maximized effects, if the field moves away from the “one-fits all” approach toward a “patient-tailored” approach. After summarizing the most commonly used rehabilitation approaches, we will focus on NIBS and highlight the factors that limit its widespread use in clinical settings. Subsequently, we will propose potential biomarkers that might help to stratify stroke patients in order to identify the individualized optimal therapy. We will discuss future methodological developments, which could open new avenues for poststroke rehabilitation, toward more patient-tailored precision medicine approaches and pathophysiologically motivated strategies.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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