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  • Dentate Gyrus Immaturity in Schizophrenia
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-12-06
  • Dysregulation of Transcription Factors: A Key Culprit Behind Neurodegenerative Disorders
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-12-06
  • Functional and Neuroanatomical Bases of Developmental Stuttering: Current Insights
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-12-06
  • Low Back Pain: The Potential Contribution of Supraspinal Motor Control and Proprioception
    Neuroscientist (IF 6.791) Pub Date : 2018-11-02
    Michael Lukas Meier; Andrea Vrana; Petra Schweinhardt

    Low back pain (LBP) is extremely common with a life-time prevalence around 75% to 84% (Thiese and others 2014) and is globally among the health conditions with the highest numbers of years lived with disability (Vos and others 2017). In most instances of LBP, no underlying pathology can be identified (Maher and others 2016), resulting in the unfortunate diagnosis of “non-specific LBP” (nsLBP). An acute episode of LBP spontaneously resolves in one third of the patients within the first 3 months; however, about 65% of the patients still experience LBP 1 year after LBP onset (Itz and others 2013). Consequently, recurrent or chronic LBP (LBP persisting for 12 weeks or more) is a common problem, with an enormous individual, economic and societal burden (Hoy and others 2014; van Tulder and others 2006). Therefore, advancing the understanding of factors contributing to the chronification of LBP is a research priority (Hartvigsen and others 2018). Among factors such as genetic, physical and psychosocial features, adaptions of motor control likely play a significant role in chronic or recurrent LBP (Hodges and others 2013) because they are associated with several important factors contributing to LBP chronification, including increased spinal tissue strains due to potential loss of trunk control and enhanced trunk muscle co-contraction, resulting in muscle fatigue (Madeleine 2010; van Dieën and others 2018b). Both factors, loss of trunk control and enhanced muscle co-contraction, have been linked with sustained mechanical loading on spinal tissues, conceivably potentiating degeneration of intervertebral discs and other tissues (Lotz and Chin 2000; Paul and others 2013; Urban and Roberts 2003; van Dieën and others 2018b).

    更新日期:2019-12-06
  • Neurocognitive and Perceptual Processing in Genetic Mouse Models of Schizophrenia: Emerging Lessons
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-12-06
  • When History Meets Neurology: Neurological Diseases of Famous People
    Neuroscientist (IF 6.791) Pub Date : 2019-03-15
    Domenico Chirchiglia; Pasquale Chirchiglia; Rosa Marotta

    This retrospective review focuses on some illustrious personalities of history, who have suffered from neurological illnesses. Neurological diseases represent about 10% of all illnesses, and therefore do not spare anyone, much less, famous people. In this review, we discuss the neurological disorders that have struck some celebrities throughout history. We briefly examine the lives of emperors, writers, poets, and musicians that have suffered from neurological diseases such as epilepsy, stroke, tumors, and other illnesses, and which caused death or disability. From a historical point of view, recollection of the lives of famous people afflicted by neurological disorders holds important lessons for future generations.

    更新日期:2019-09-26
  • Contributions of Neuroscience Knowledge to Teachers and Their Practice
    Neuroscientist (IF 6.791) Pub Date : 2019-03-21
    Janet M. Dubinsky; S. Selcen Guzey; Marc S. Schwartz; Gillian Roehrig; Carrie MacNabb; Astrid Schmied; Vicki Hinesley; Mary Hoelscher; Michael Michlin; Lee Schmitt; Charlene Ellingson; Zhengsi Chang; Janice L. Cooper

    While neuroscience has elucidated the mechanisms underpinning learning and memory, accurate dissemination of this knowledge to teachers and educators has been limited. This review focuses on teacher professional development in neuroscience that harnessed the power of active-learning strategies and best educational practices resulting in increased teacher and student understanding of cognition and brain function. For teachers, the experience of learning a novel subject in an active manner enabled them to subsequently teach using similar strategies. Most important, participants viewed neuroscience as a frame for understanding why active-learning pedagogies work to engage and motivate students. Teachers themselves made connections applying neuroscience concepts to understand why learner-centered pedagogies are effective in promoting higher order thinking and deep learning in their students. Teachers planned and embraced pedagogies involving modeling, experimentation, discussion, analysis, and synthesis, increasing classroom cognitive engagement. Comprehending that everyone is in charge of changing their own brains is a tremendously powerful idea that may motivate science and non-science teachers to provide students opportunities to actively engage with content. Neuroscience courses for preservice and in-service teachers, provided as collaborations between scientists and teacher educators, can result in improved science education, pedagogy, and understanding of neuroscience.

    更新日期:2019-09-26
  • Distinct Calcium Sources Define Compartmentalized Synaptic Signaling Domains
    Neuroscientist (IF 6.791) Pub Date : 2019-08-02
    Jessica A. Fawley; Michael C. Andresen

    Nervous system communication relies on neurotransmitter release for synaptic transmission between neurons. Neurotransmitter is contained within vesicles in presynaptic terminals and intraterminal calcium governs the fundamental step of their release into the synaptic cleft. Despite a common dependence on calcium, synaptic transmission and its modulation varies highly across the nervous system. The precise mechanisms that underlie this heterogeneity, however, remain unclear. The present review highlights recent data that reveal vesicles sourced from separate pools define discrete modes of release. A rich diversity of regulatory machinery may further distinguish the different forms of vesicle release, including presynaptic proteins involved in trafficking, alignment, and exocytosis. These multiple vesicle release mechanisms and vesicle pools likely depend on the arrangement of vesicles in relation to specific calcium entry pathways that create compartmentalized spheres of calcium influence (i.e., domains). This diversity permits release specialization. This review details examples of how individual neurons rely on multiple calcium sources and unique regulatory schemes to provide differential release and discrete modulation of neurotransmitter release from specific vesicle pools—as part of network signal integration.

    更新日期:2019-09-26
  • ER Stress, CREB, and Memory: A Tangled Emerging Link in Disease
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-26
  • Brain-Derived Neurotrophic Factor (BDNF): Novel Insights into Regulation and Genetic Variation
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-26
  • Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-26
  • The Striatum’s Role in Executing Rational and Irrational Economic Behaviors
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-26
  • The Urge to Decide and Act: Implications for Brain Function and Dysfunction
    Neuroscientist (IF 6.791) Pub Date : 2019-05-08
    Matthew A. Carland; David Thura; Paul Cisek

    Humans and other animals are motivated to act so as to maximize their subjective reward rate. Here, we propose that reward rate maximization is accomplished by adjusting a context-dependent “urgency signal,” which influences both the commitment to a developing action choice and the vigor with which the ensuing action is performed. We review behavioral and neurophysiological data suggesting that urgency is controlled by projections from the basal ganglia to cerebral cortical regions, influencing neural activity related to decision making as well as activity related to action execution. We also review evidence suggesting that different individuals possess specific policies for adjusting their urgency signal to particular contextual variables, such that urgency constitutes an individual trait which jointly influences a wide range of behavioral measures commonly related to the overall quality and hastiness of one’s decisions and actions. Consequently, we argue that a central mechanism for reward rate maximization provides a potential link between personality traits such as impulsivity, as well as some of the motivation-related symptomology of clinical disorders such as depression and Parkinson’s disease.

    更新日期:2019-09-26
  • The Expanding Clinical Universe of Polyglutamine Disease
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-26
  • Mitochondrial CHCHD2 and CHCHD10: Roles in Neurological Diseases and Therapeutic Implications
    Neuroscientist (IF 6.791) Pub Date : 2019-09-16
    Wei Zhou; Dongrui Ma; Eng-King Tan

    CHCHD2 mutations have been identified in various neurological diseases such as Parkinson’s disease (PD), frontotemporal dementia (FTD), and Alzheimer’s disease (AD). It is also the first mitochondrial gene whose mutations lead to PD. CHCHD10 is a homolog of CHCHD2; similar to CHCHD2, various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD and AD, with a high frequency of CHCHD10 mutations found in motor neuron diseases. Functionally, CHCHD2 and CHCHD10 have been demonstrated to interact with each other in mitochondria. Recent studies link the biological functions of CHCHD2 to the MICOS complex (mitochondrial inner membrane organizing system). Multiple experimental models suggest that CHCHD2 maintains mitochondrial cristae and disease-associated CHCHD2 mutations function in a loss-of-function manner. However, both CHCHD2 and CHCHD10 knockout mouse models appear phenotypically normal, with no obvious mitochondrial defects. Strategies to maintain or enhance mitochondria cristae could provide opportunities to correct the associated cellular defects in disease state and unravel potential novel targets for CHCHD2-linked neurological conditions.

    更新日期:2019-09-18
  • Amyloid Plaques of Alzheimer’s Disease as Hotspots of Glutamatergic Activity
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-14
  • Twitches, Blinks, and Fidgets: Important Generators of Ongoing Neural Activity
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-14
  • Region-Specific Phenotypes of Microglia: The Role of Local Regulatory Cues
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-09-14
  • Oligodendrocyte Bioenergetics in Health and Disease
    Neuroscientist (IF 6.791) Pub Date : 2018-08-20
    Lauren Rosko; Victoria N. Smith; Reiji Yamazaki; Jeffrey K. Huang

    During peak myelination, an oligodendrocyte expands its membrane three times its weight per day and eventually supports a membrane weight of 100 times its cell body (Bradl and Lassmann 2010; McLaurin and Yong 1995). Oligodendrocytes consume large amounts of metabolites, such as glucose and lactate, for the energy-demanding tasks of myelination during development and remyelination after demyelinating injury (Fig. 1). The significant energy and metabolic substrate demands for myelination are supplied from the diet or from reserves of protein, fat, and glycogen that must later be replaced. It is estimated that 3.3 × 1023 ATP molecules are needed for oligodendrocytes to synthesize just one gram of myelin (Harris and Attwell 2012). Despite the large initial energy demands necessary for myelin synthesis, mature myelin is energetically favorable because it reduces the energy demands required for action potentials and accelerates nerve conduction. In addition to their role in myelination, oligodendrocytes facilitate the transfer of metabolites to fuel neurons and support the integrity of myelinated axons (Griffiths and others 1998). Axons have high energy costs since they must maintain Na+/K+-ATPase pumps and restore ionic gradients (Niven and Laughlin 2008). Na+/K+-ATPase pumps were previously suggested to be localized at the nodes of Ranvier; however, pumps are now known to also be dispersed throughout myelin internodes (McGrail and others 1991). Since humans have axons that can extend up to more than a meter in length, neural processing within these long-range, myelinated axons is metabolically expensive. Myelin sheaths also act as a barrier, restricting access to extracellular metabolites (Nave 2010). This barrier underscores the importance of oligodendrocytes in energy passage into the axon. Like axons, oligodendrocytes have high energy demands and are extremely vulnerable to energy deprivation (Pantoni and others 1996). Oligodendrocytes’ particular susceptibility to energy deprivation is evidenced by the fact that occlusion of the middle cerebral artery leads to oligodendrocyte swelling within 30 minutes and chromatin condensation within six hours (Pantoni and others 1996). These oligodendrocyte changes precede neuronal death by several hours, suggesting that energetic dysfunction in oligodendrocytes contributes to neuronal pathology. Therefore, it is important to understand how oligodendrocyte bioenergetics regulates normal brain function and how their dysfunction contributes to demyelinating diseases such as multiple sclerosis (MS).

    更新日期:2019-09-14
  • GABAergic Interneurons in Seizures: Investigating Causality With Optogenetics
    Neuroscientist (IF 6.791) Pub Date : 2018-10-15
    Vincent Magloire; Marion S. Mercier; Dimitri M. Kullmann; Ivan Pavlov

    Epilepsy affects approximately 1% of the population, and in developed countries up to 30% of patients continue to experience seizures despite optimal antiepileptic medication (Schmidt and Loscher 2005). There is therefore an urgent need to identify novel therapeutic targets and develop new treatment strategies. Focal seizures are widely considered to arise from a disturbance of the excitation/inhibition balance, and in particular a failure of the GABAergic inhibitory system. In support of this view, reducing inhibition experimentally by blocking GABAergic neurotransmission induces epileptiform activity both in vitro and in animal models (Pitkänen and others 2005), while drugs that potentiate inhibition suppress seizures and are widely used clinically (Mula 2011). Furthermore, a breakdown of feed-forward inhibition has been shown to occur during the propagation of the seizure front across the cortex (Schevon and others 2012; Trevelyan and others 2006; Trevelyan and others 2007). Although the evidence for a failure of GABAergic inhibition is compelling, it must be interpreted in the context of a highly diverse population of interneurons. Indeed, more than 20 different interneuron subtypes have been identified in the cortex, displaying a wide range of electrophysiological properties, morphologies, genetic markers, innervation patterns and GABAergic signaling profiles (Ascoli and others 2008; Jiang and others 2015). Molecular markers, such as the calcium-binding protein parvalbumin (PV) and the neuropeptides somatostatin (SOM) and vasointestinal peptide (VIP), have been used to distinguish between interneuron subtypes that primarily mediate somatic inhibition, dendritic inhibition, and disinhibition, respectively (Box 1, Tremblay and others 2016). Advances in Cre-Lox technology, optogenetics, and imaging methods allow these different types of inhibition to be selectively manipulated, enabling a cellular and spatiotemporal resolution that was not previously achievable using pharmacological agents. However, while optogenetic inhibition of principal neuron activity has been successfully employed to curtail seizures in different models (Chiang and others 2014; Krook-Magnuson and others 2013; Paz and others 2012; Wykes and others 2012), optogenetic manipulation of interneuronal activity has thus far generated mixed results, which may in part be due to the dynamic nature of epileptic states. In this review, we aim to bring together these apparently conflicting findings, and to explain them in the light of key experimental differences: specifically, we distinguish between studies investigating interictal discharges and those that address seizures per se, and between findings on the generation of seizure activity and on its maintenance. We also compare the involvement of different GABAergic cell subtypes and examine the various optogenetic stimulation protocols that have been used.

    更新日期:2019-09-14
  • Thinking Outside the Box (and Arrow): Current Themes in Striatal Dysfunction in Movement Disorders
    Neuroscientist (IF 6.791) Pub Date : 2018-10-31
    Joshua L. Plotkin; Joshua A. Goldberg

    Until the early 1970s, medical practitioners were being taught that the striatum (caudate and putamen nuclei) is part of the extrapyramidal motor system and exerts a “steadying influence” (Wilson 1912) on lower motor neurons via a putative descending projection (Denny-Brown 1962; Kemp and Powell 1971). As a result of research conducted over the next two decades, in what may be called the Golden Age of basal ganglia (BG) research, this vague and imprecise description was supplanted in medical and neuroscience textbooks by the direct versus indirect pathway model (also known as the “box-and-arrow” model) of BG physiology and pathophysiology (Albin and others 1989; DeLong 1990). This model organized what had been learned during this period about the gross anatomy and physiology of the BG into a comprehensive model of how two mutually antagonistic pathways gate action and how movement disorders could be conceptualized as resulting from an imbalance between them.

    更新日期:2019-09-14
  • Modeling Emergent Properties in the Brain Using Tissue Models to Investigate Neurodegenerative Disease
    Neuroscientist (IF 6.791) Pub Date : 2019-09-13
    Alexander R. Harris; Patrick McGivern; Lezanne Ooi

    Here we describe emergent properties of the brain and the key challenges associated with modelling them in vitro. Modeling emergent properties of the brain will provide insights into brain function, development, and disease.

    更新日期:2019-09-14
  • The Complex Relationships between Sex and the Brain
    Neuroscientist (IF 6.791) Pub Date : 2019-09-11
    Daphna Joel; Alicia Garcia-Falgueras; Dick Swaab

    In the past decennia, our understanding of the sexual differentiation of the mammalian brain has dramatically changed. The simple model according to which testosterone masculinizes the brain of males away from a default female form, was replaced with a complex scenario, according to which sex effects on the brain of both females and males are exerted by genetic, hormonal, and environmental factors. These factors act via multiple partly independent mechanisms that may vary according to internal and external factors. These observations led to the “mosaic” hypothesis—the expectation of high variability in the degree of “maleness”/“femaleness” of different features within a single brain. Here, we briefly review animal data that form the basis of current understanding of sexual differentiation; present, in this context, the results of co-analyses of human brain measures obtained by magnetic resonance imaging or postmortem; discuss criticisms and controversies of the mosaic hypothesis and implications for research; and conclude that co-analysis of several (preferably, many) features and going back from the group level to that of the individual would advance our understanding of the relations between sex and the brain in health and disease.

    更新日期:2019-09-11
  • Patterning the Vertebrate Retina with Morphogenetic Signaling Pathways
    Neuroscientist (IF 6.791) Pub Date : 2019-09-11
    Marcos J. Cardozo; María Almuedo-Castillo; Paola Bovolenta

    The primordium of the vertebrate eye is composed of a pseudostratified and apparently homogeneous neuroepithelium, which folds inward to generate a bilayered optic cup. During these early morphogenetic events, the optic vesicle is patterned along three different axes—proximo-distal, dorso-ventral, and naso-temporal—and three major domains: the neural retina, the retinal pigment epithelium (RPE), and the optic stalk. These fundamental steps that enable the subsequent development of a functional eye, entail the precise coordination among genetic programs. These programs are driven by the interplay of signaling pathways and transcription factors, which progressively dictate how each tissue should evolve. Here, we discuss the contribution of the Hh, Wnt, FGF, and BMP signaling pathways to the early patterning of the retina. Comparative studies in different vertebrate species have shown that their morphogenetic activity is repetitively used to orchestrate the progressive specification of the eye with evolutionary conserved mechanisms that have been adapted to match the specific need of a given species.

    更新日期:2019-09-11
  • From Conditioning to Emotion: Translating Animal Models of Learning to Human Psychopathology
    Neuroscientist (IF 6.791) Pub Date : 2019-08-05
    Aaron S. Heller

    Emotional responses are not static but change as a consequence of learning. Organisms adapt to emotional events and these adaptations influence the way we think, behave, and feel when we encounter similar situations in the future. Integrating recent work from rodent models and research on human psychopathology, this article lays out a model describing how affective events cause learning and can lead to anxiety and depression: affective events are linked to conditioned stimuli and contexts. Affective experiences entrain oscillatory synchrony across distributed neural circuits, including the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens, which form associations that constitute the basis of emotional memories. Consolidation of these experiences appears to be supported by replay in the hippocampus—a process by which hippocampal firing patterns recreate the firing pattern that occurred previously. Generalization of learning occurs to never before experienced contexts when associations form across distinct but related conditioned stimuli. The process of generalization, which requires cortical structures, can cause memories to become abstracted. During abstraction, the latent, overlapping features of the learned associations remain and result in the formation of schemas. Schemas are adaptive because they facilitate the rapid processing of conditioned stimuli and prime behavioral, cognitive, and affective responses that are the manifestations of the accumulation of an individual’s conditioned experiences. However, schemas can be maladaptive when the generalization of aversive emotional responses are applied to stimuli and contexts in which affective reactions are unnecessary. I describe how this process can lead to not only mood and anxiety disorders but also psychotherapeutic treatment.

    更新日期:2019-08-06
  • Plastic Adaptation to Pathology in Psychiatry: Are Patients with Psychiatric Disorders Pathological Experts?
    Neuroscientist (IF 6.791) Pub Date : 2019-08-05
    Ali Amad; Paul Expert; Louis-David Lord; Thomas Fovet; Pierre A. Geoffroy

    Psychiatric disorders share the same pattern of longitudinal evolution and have courses that tend to be chronic and recurrent. These aspects of chronicity and longitudinal evolution are currently studied under the deficit-oriented neuroprogression framework. Interestingly, considering the plasticity of the brain, it is also necessary to emphasize the bidirectional nature of neuroprogression. We review evidence highlighting alterations of the brain associated with the longitudinal evolution of psychiatric disorders from the framework of neuroplastic adaptation to pathology. This new framework highlights that substantial plasticity and remodeling may occur beyond the classic deficit-oriented neuroprogressive framework, which has been associated with progressive loss of gray matter thickness, decreased brain connectivity, and chronic inflammation. We also integrate the brain economy concept in the neuroplastic adaptation to pathology framework, emphasizing that to preserve its economy, i.e. function, the brain learns how to cope with the disease by adapting its architecture. Neuroplastic adaptation to pathology is a proposition for a paradigm shift to overcome the shortcomings of traditional psychiatric diagnostic boundaries; this approach can disentangle both the specific pathophysiology of psychiatric symptoms and the adaptation to pathology, thus offering a new framework for both diagnosis and treatment.

    更新日期:2019-08-06
  • Regions and Connections: Complementary Approaches to Characterize Brain Organization and Function
    Neuroscientist (IF 6.791) Pub Date : 2019-07-14
    Corey Horien; Abigail S. Greene; R. Todd Constable; Dustin Scheinost

    Human neuroscience research continues to reveal the neural processes underlying high-level cognitive functions (Turk-Browne 2013). Functional magnetic resonance imaging (fMRI)-based analyses, by capturing patterns of brain activity that may be local or widespread in space, are uniquely suited to study such neural representations and, by extension, brain organization.

    更新日期:2019-07-15
  • What Guides Us to Neurally and Behaviorally Align With Anyone Specific? A Neurobiological Model Based on fNIRS Hyperscanning Studies
    Neuroscientist (IF 6.791) Pub Date : 2019-07-11
    Hila Z. Gvirts; Rotem Perlmutter

    An emerging body of hyperscanning functional near-infrared spectroscopy (fNIRS) research shows interbrain neural synchrony (IBS) during different forms of social interaction. Here we review the recent literature and propose several factors that facilitate IBS, leading us to ask the following question: In a world full of people and opportunities to synchronize with them, what directs our neural and behavioral alignment with anyone specific? We suggest that IBS between what we deem the “mutual social attention systems” of interacting partners—that is, the coupling between participants’ temporoparietal junctions and/or prefrontal cortices—facilitates and enhances the ability to tune in to the specific interaction, its participants and its goals. We propose that this process is linked to social alignment, reinforcing one another to facilitate successful and lucrative social interactions. We further suggest that neurochemical mechanisms of dopamine and oxytocin underlie the activation of this suggested loop. Finally, we suggest possible directions for future studies, emphasizing the need to develop a brain-to-brain neurofeedback system with IBS between the mutual social attention systems of the participants as the direct regulating target.

    更新日期:2019-07-12
  • How Reward and Aversion Shape Motivation and Decision Making: A Computational Account
    Neuroscientist (IF 6.791) Pub Date : 2019-03-13
    Jeroen P. H. Verharen; Roger A. H. Adan; Louk J. M. J. Vanderschuren

    Processing rewarding and aversive signals lies at the core of many adaptive behaviors, including value-based decision making. The brain circuits processing these signals are widespread and include the prefrontal cortex, amygdala and striatum, and their dopaminergic innervation. In this review, we integrate historic findings on the behavioral and neural mechanisms of value-based decision making with recent, groundbreaking work in this area. On the basis of this integrated view, we discuss a neuroeconomic framework of value-based decision making, use this to explain the motivation to pursue rewards and how motivation relates to the costs and benefits associated with different courses of action. As such, we consider substance addiction and overeating as states of altered value-based decision making, in which the expectation of reward chronically outweighs the costs associated with substance use and food consumption, respectively. Together, this review aims to provide a concise and accessible overview of important literature on the neural mechanisms of behavioral adaptation to reward and aversion and how these mediate motivated behaviors.

    更新日期:2019-07-05
  • Function of Lymphocytes in Oligodendrocyte Development
    Neuroscientist (IF 6.791) Pub Date : 2019-03-08
    Shogo Tanabe; Toshihide Yamashita

    Oligodendrocytes generate myelin sheaths to promote rapid neurotransmission in the central nervous system (CNS). During brain development, oligodendrocyte precursor cells (OPCs) are generated in the medial ganglionic eminence, lateral ganglionic eminence, and dorsal pallium. OPCs proliferate and migrate throughout the CNS at the embryonic stage. After birth, OPCs differentiate into mature oligodendrocytes, which then insulate axons. Oligodendrocyte development is regulated by the extrinsic environment including neurons, astrocytes, and immune cells. During brain development, B lymphocytes are present in the meningeal space, and are involved in oligodendrocyte development by promoting OPC proliferation. T lymphocytes mediate oligodendrocyte development during the remyelination process. Moreover, a subset of microglia contributes to oligodendrocyte development during the neonatal periods. Therefore, the immune system, especially lymphocytes and microglia, contribute to oligodendrocyte development during brain development and remyelination.

    更新日期:2019-07-05
  • Probing the Link Between Perception and Oscillations: Lessons from Transcranial Alternating Current Stimulation
    Neuroscientist (IF 6.791) Pub Date : 2019-02-07
    Yuranny Cabral-Calderin; Melanie Wilke

    Perception is a constructive process, which does not rely exclusively on the incoming sensory information but requires the interaction between this information and the internal state of the brain including predictions, thoughts, and beliefs (Long and Toppino 2004; Picard and Friston 2014).

    更新日期:2019-07-05
  • Protein Translation and Psychiatric Disorders
    Neuroscientist (IF 6.791) Pub Date : 2019-07-04
    Sophie Laguesse; Dorit Ron

    Although historically research has focused on transcription as the central governor of protein expression, protein translation is now increasingly being recognized as a major factor for determining protein levels within cells. The central nervous system relies on efficient updating of the protein landscape. Thus, coordinated regulation of mRNA localization, initiation, or termination of translation is essential for proper brain function. In particular, dendritic protein synthesis plays a key role in synaptic plasticity underlying learning and memory as well as cognitive processes. Increasing evidence suggests that impaired mRNA translation is a common feature found in numerous psychiatric disorders. In this review, we describe how malfunction of translation contributes to development of psychiatric diseases, including schizophrenia, major depression, bipolar disorder, and addiction.

    更新日期:2019-07-05
  • TGFβ1: Friend or Foe During Recovery in Encephalopathy
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Human Stem Cell–Derived Models: Lessons for Autoimmune Diseases of the Nervous System
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Intracellular Ca2+ Release and Synaptic Plasticity: A Tale of Many Stores
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Microglia-Astrocyte Crosstalk: An Intimate Molecular Conversation
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Purkinje Cell Representations of Behavior: Diary of a Busy Neuron
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Emotions and the Right Hemisphere: Can New Data Clarify Old Models?
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • The National Undergraduate Neuroanatomy Competition: Lessons Learned from Partnering with Students to Innovate Undergraduate Neuroanatomy Education
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Brain Injury–Mediated Neuroinflammatory Response and Alzheimer’s Disease
    Neuroscientist (IF 6.791) Pub Date : 2019-05-16
    Duraisamy Kempuraj; Mohammad Ejaz Ahmed; Govindhasamy Pushpavathi Selvakumar; Ramasamy Thangavel; Arshdeep S. Dhaliwal; Iuliia Dubova; Shireen Mentor; Keerthivaas Premkumar; Daniyal Saeed; Haris Zahoor; Sudhanshu P. Raikwar; Smita Zaheer; Shankar S. Iyer; Asgar Zaheer

    Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer’s disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.

    更新日期:2019-05-16
  • Synaptotagmins: Beyond Presynaptic Neurotransmitter Release
    Neuroscientist (IF 6.791) Pub Date : 2019-05-03
    Xuanang Wu; Shaoqin Hu; Xinjiang Kang; Changhe Wang

    Synaptotagmins (Syts) are well-established primary Ca2+ sensors to initiate presynaptic neurotransmitter release. They also play critical roles in the docking, priming, and fusion steps of exocytosis, as well as the tightly coupled exo-endocytosis, in presynapses. A recent study by Awasthi and others (2019) shows that Syt3 Ca2+-dependently modulates the postsynaptic receptor endocytosis and thereby promotes the long-term depression (LTD) and the decay of long-term potentiation (LTP). This work highlights the importance of Syt3 in modulating long-term synaptic plasticity and, importantly, extends the function of Syt proteins from presynaptic neurotransmitter release to a new promising postsynaptic receptor internalization.

    更新日期:2019-05-16
  • The Legacy of Rita Levi-Montalcini: From Nerve Growth Factor to Neuroinflammation
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-05-16
  • Scientists, Instruments, and Even Brains in Transfer: German-Spanish Postwar Networks and the Construction of the Neuroendocrine System (1952-1960)
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • New Insights into the Neurobiology of Restless Legs Syndrome
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • Mitochondrial Zn2+ Accumulation: A Potential Trigger of Hippocampal Ischemic Injury
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • Brain-Machine Interfaces: Powerful Tools for Clinical Treatment and Neuroscientific Investigations
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • Fluid Dynamics Inside the Brain Barrier: Current Concept of Interstitial Flow, Glymphatic Flow, and Cerebrospinal Fluid Circulation in the Brain
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • Ammon’s Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-03-12
  • CNS Injury: Posttranslational Modification of the Tau Protein as a Biomarker
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • Noncoding RNAs and Stroke
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • Dendritic Spine Elimination: Molecular Mechanisms and Implications
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • The Subthalamic Nucleus: Unravelling New Roles and Mechanisms in the Control of Action
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • Exercise-Induced Neuroplasticity: A Mechanistic Model and Prospects for Promoting Plasticity
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • Tracking Neuronal Connectivity from Electric Brain Signals to Predict Performance
    Neuroscientist (IF 6.791) 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.

    更新日期:2019-01-11
  • Are We “Motorically” Wired to Others? High-Level Motor Computations and Their Role in Autism
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
  • Orientation Encoding and Viewpoint Invariance in Face Recognition: Inferring Neural Properties from Large-Scale Signals
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
  • Neural Oscillations Orchestrate Multisensory Processing
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
  • Epigenetic Control of Schwann Cells
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
  • The Ubiquitin-Proteasome System and Memory: Moving Beyond Protein Degradation
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
  • Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons
    Neuroscientist (IF 6.791) 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.

    更新日期:2018-11-08
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