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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 it 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.
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.
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.
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.
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.
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.
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.
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.
Fluid Dynamics Inside the Brain Barrier 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.
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.
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.
Polycomb Repressive Complex 2: Emerging Roles in the Central Nervous System Neuroscientist (IF 7.461) Pub Date : 2017-12-14 Pei-Pei Liu; Ya-Jie Xu; Zhao-Qian Teng; Chang-Mei Liu
The polycomb repressive complex 2 (PRC2) is responsible for catalyzing both di- and trimethylation of histone H3 at lysine 27 (H3K27me2/3). The subunits of PRC2 are widely expressed in the central nervous system (CNS). PRC2 as well as H3K27me2/3, play distinct roles in neuronal identity, proliferation and differentiation of neural stem/progenitor cells, neuronal morphology, and gliogenesis. Mutations or dysregulations of PRC2 subunits often cause neurological diseases. Therefore, PRC2 might represent a common target of different pathological processes that drive neurodegenerative diseases. A better understanding of the intricate and complex regulatory networks mediated by PRC2 in CNS will help to develop new therapeutic approaches and to generate specific brain cell types for treating neurological diseases.
Noninvasive Stimulation of the Human Brain: Activation of Multiple Cortical Circuits Neuroscientist (IF 7.461) Pub Date : 2017-06-29 Vincenzo Di Lazzaro; John Rothwell; Marco Capogna
Noninvasive brain stimulation methods, such as transcranial electric stimulation and transcranial magnetic stimulation are widely used tools for both basic research and clinical applications. However, the cortical circuits underlying their effects are poorly defined. Here we review the current knowledge based on data mostly coming from experiments performed on human subjects, and also to a lesser extent on rodent or primate models. The data suggest that multiple mechanisms are likely to be involved, such as the direct activation of layer V pyramidal neurons, but also of different types of GABAergic interneurons. In this regard, we propose a key role for a specific type of interneuron known as neurogliaform cell.
Plasticity in the Working Memory System: Life Span Changes and Response to Injury Neuroscientist (IF 7.461) Pub Date : 2017-07-08 Sean Froudist-Walsh; Diana López-Barroso; María José Torres-Prioris; Paula L. Croxson; Marcelo L. Berthier
Working memory acts as a key bridge between perception, long-term memory, and action. The brain regions, connections, and neurotransmitters that underlie working memory undergo dramatic plastic changes during the life span, and in response to injury. Early life reliance on deep gray matter structures fades during adolescence as increasing reliance on prefrontal and parietal cortex accompanies the development of executive aspects of working memory. The rise and fall of working memory capacity and executive functions parallels the development and loss of neurotransmitter function in frontal cortical areas. Of the affected neurotransmitters, dopamine and acetylcholine modulate excitatory-inhibitory circuits that underlie working memory, are important for plasticity in the system, and are affected following preterm birth and adult brain injury. Pharmacological interventions to promote recovery of working memory abilities have had limited success, but hold promise if used in combination with behavioral training and brain stimulation. The intense study of working memory in a range of species, ages and following injuries has led to better understanding of the intrinsic plasticity mechanisms in the working memory system. The challenge now is to guide these mechanisms to better improve or restore working memory function.
Harmonic Brain Modes: A Unifying Framework for Linking Space and Time in Brain Dynamics Neuroscientist (IF 7.461) Pub Date : 2017-09-01 Selen Atasoy; Gustavo Deco; Morten L. Kringelbach; Joel Pearson
A fundamental characteristic of spontaneous brain activity is coherent oscillations covering a wide range of frequencies. Interestingly, these temporal oscillations are highly correlated among spatially distributed cortical areas forming structured correlation patterns known as the resting state networks, although the brain is never truly at “rest.” Here, we introduce the concept of harmonic brain modes—fundamental building blocks of complex spatiotemporal patterns of neural activity. We define these elementary harmonic brain modes as harmonic modes of structural connectivity; that is, connectome harmonics, yielding fully synchronous neural activity patterns with different frequency oscillations emerging on and constrained by the particular structure of the brain. Hence, this particular definition implicitly links the hitherto poorly understood dimensions of space and time in brain dynamics and its underlying anatomy. Further we show how harmonic brain modes can explain the relationship between neurophysiological, temporal, and network-level changes in the brain across different mental states (wakefulness, sleep, anesthesia, psychedelic). Notably, when decoded as activation of connectome harmonics, spatial and temporal characteristics of neural activity naturally emerge from the interplay between excitation and inhibition and this critical relation fits the spatial, temporal, and neurophysiological changes associated with different mental states. Thus, the introduced framework of harmonic brain modes not only establishes a relation between the spatial structure of correlation patterns and temporal oscillations (linking space and time in brain dynamics), but also enables a new dimension of tools for understanding fundamental principles underlying brain dynamics in different states of consciousness.
Multiple System Atrophy: Many Lessons from the Transcriptome Neuroscientist (IF 7.461) Pub Date : 2017-08-03 Ashton Curry-Hyde; Bei Jun Chen; Uwe Ueberham; Thomas Arendt; Michael Janitz
Multiple system atrophy (MSA) is a complex, multifactorial, debilitating neurodegenerative disease that is often misdiagnosed and misunderstood. MSA has two subclasses, MSA-P and MSA-C, defined by the dominance of parkinsonism or cerebellar dysfunction in the earlier stages of disease, coupled with dysautonomia. This distinction between subclasses becomes largely redundant as the disease progresses. Aggregation of α-synuclein is a clinical marker used to confirm MSA diagnoses, which can only be performed postmortem. Transcriptome profiling provides in-depth information about the diseased state and can contribute to further understanding of MSA, enabling easier and more rapid diagnosis as well as contributing to improving the quality of life of people with MSA. Currently, there is no method of diagnosing MSA with certainty, and there is no cure for this disease. This review provides an update on current advances in investigations of molecular pathology of MSA with particular focus on perturbation of individual gene expression and MSA transcriptome.
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.
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 and we discuss their implication in neuropsychiatric and neurodegenerative disease.
The Axonal Cytoskeleton and the Assembly of Nodes of Ranvier Neuroscientist (IF 7.461) Pub Date : 2017-05-23 Aniket Ghosh; Diane L. Sherman; Peter J. Brophy
Vertebrate nervous systems rely on rapid nerve impulse transmission to support their complex functions. Fast conduction depends on ensheathment of nerve axons by myelin-forming glia and the clustering of high concentrations of voltage-gated sodium channels (Nav) in the axonal gaps between myelinated segments. These gaps are the nodes of Ranvier. Depolarization of the axonal membrane initiates the action potential responsible for impulse transmission, and the Nav help ensure that this is restricted to nodes. In the central nervous system, the formation of nodes and the clustering of Nav in nodal complexes is achieved when oligodendrocytes extend their processes and ultimately ensheath axons with myelin. However, the mechanistic relationship between myelination and the formation of nodal complexes is unclear. Here we review recent work in the central nervous system that shows that axons, by assembling distinct cytoskeletal interfaces, are not only active participants in oligodendrocyte process migration but are also significant contributors to the mechanisms by which myelination causes Nav clustering. We also discuss how the segregation of membrane protein complexes through their interaction with distinct cytoskeletal complexes may play a wider role in establishing surface domains in axons.
Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease Neuroscientist (IF 7.461) Pub Date : 2017-06-08 Amar N. Kar; Seung Joon Lee; Jeffery L. Twiss
Intra-axonal protein synthesis has been shown to play critical roles in both development and repair of axons. Axons provide long-range connectivity in the nervous system, and disruption of their function and/or structure is seen in several neurological diseases and disorders. Axonally synthesized proteins or losses in axonally synthesized proteins contribute to neurodegenerative diseases, neuropathic pain, viral transport, and survival of axons. Increasing sensitivity of RNA detection and quantitation coupled with methods to isolate axons to purity has shown that a surprisingly complex transcriptome exists in axons. This extends across different species, neuronal populations, and physiological conditions. These studies have helped define the repertoire of neuronal mRNAs that can localize into axons and imply previously unrecognized functions for local translation in neurons. Here, we review the current state of transcriptomics studies of isolated axons, contrast axonal mRNA profiles between different neuronal types and growth states, and discuss how mRNA transport into and translation within axons contribute to neurological disorders.
Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis Neuroscientist (IF 7.461) Pub Date : 2017-06-05 Nailya Lotfullina; Roustem Khazipov
Ethanol induces massive neuroapoptosis in the developing brain. One of the main hypotheses that has been put forward to explain the deleterious actions of ethanol in the immature brain involves an inhibition of neuronal activity. Here, we review recent evidence for this hypothesis obtained in the somatosensory cortex and hippocampus of neonatal rodents. In both structures, ethanol strongly inhibits brain activity. At the doses inducing massive neuroapoptosis, ethanol completely suppresses the early activity patterns of spindle-bursts and gamma oscillations in the neocortex and the early sharp-waves in the hippocampus. The inhibitory effects of ethanol decrease with age and in adult animals, ethanol only mildly depresses neuronal firing and induces delta-wave activity. Suppression of cortical activity in neonatal animals likely involves inhibition of the myoclonic twitches, an important physiological trigger for the early activity bursts, and inhibition of the thalamocortical and intracortical circuits through a potentiation of GABAergic transmission and an inhibition of N-methyl-d-aspartate (NMDA) receptors, that is in keeping with the neuroapoptotic effects of other agents acting on GABA and NMDA receptors. These findings provide support for the hypothesis that the ethanol-induced inhibition of cortical activity is an important pathophysiological mechanism underlying massive neuroapoptosis induced by ethanol in the developing brain.
Nuclear-Encoded Mitochondrial mRNAs: A Powerful Force in Axonal Growth and Development Neuroscientist (IF 7.461) Pub Date : 2017-06-14 Jenna R. Gale; Armaz Aschrafi; Anthony E. Gioio; Barry B. Kaplan
Axons, their growth cones, and synaptic nerve terminals are neuronal subcompartments that have high energetic needs. As such, they are enriched in mitochondria, which supply the ATP necessary to meet these demands. To date, a heterogeneous population of nuclear-encoded mitochondrial mRNAs has been identified in distal axons and growth cones. Accumulating evidence suggests that the local translation of these mRNAs is required for mitochondrial maintenance and axonal viability. Here, we review evidence that suggests a critical role for axonal translation of nuclear-encoded mitochondrial mRNAs in axonal growth and development. Additionally, we explore the role that site-specific translation at the mitochondria itself may play in this process. Finally, we briefly review the clinical implications of dysregulation of local translation of mitochondrial-related mRNAs in neurodevelopmental disorders.
The Subventricular Zone: A Key Player in Human Neocortical Development Neuroscientist (IF 7.461) Pub Date : 2017-02-13 J. Alberto Ortega; Fani Memi; Nevena Radonjic; Radmila Filipovic; Inseyah Bagasrawala; Nada Zecevic; Igor Jakovcevski
One of the main characteristics of the developing brain is that all neurons and the majority of macroglia originate first in the ventricular zone (VZ), next to the lumen of the cerebral ventricles, and later on in a secondary germinal area above the VZ, the subventricular zone (SVZ). The SVZ is a transient compartment mitotically active in humans for several gestational months. It serves as a major source of cortical projection neurons as well as an additional source of glial cells and potentially some interneuron subpopulations. The SVZ is subdivided into the smaller inner (iSVZ) and the expanded outer SVZ (oSVZ). The enlargement of the SVZ and, in particular, the emergence of the oSVZ are evolutionary adaptations that were critical to the expansion and unique cellular composition of the primate cerebral cortex. In this review, we discuss the cell types and organization of the human SVZ during the first half of the 40 weeks of gestation that comprise intrauterine development. We focus on this period as it is when the bulk of neurogenesis in the human cerebral cortex takes place. We consider how the survival and fate of SVZ cells depend on environmental influences, by analyzing the results from in vitro experiments with human cortical progenitor cells. This in vitro model is a powerful tool to better understand human neocortex formation and the etiology of neurodevelopmental disorders, which in turn will facilitate the design of targeted preventive and/or therapeutic strategies.
Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression? Neuroscientist (IF 7.461) Pub Date : 2017-05-17 Gonca Bayraktar; Michael R. Kreutz
DNMT3A and 3B are the main de novo DNA methyltransferases (DNMTs) in the brain that introduce new methylation marks to non-methylated DNA in postmitotic neurons. DNA methylation is a key epigenetic mark that is known to regulate important cellular processes in neuronal development and brain plasticity. Accumulating evidence disclosed rapid and dynamic changes in DNA methylation of plasticity-relevant genes that are important for learning and memory formation. To understand how DNMTs contribute to brain function and how they are regulated by neuronal activity is a prerequisite for a deeper appreciation of activity-dependent gene expression in health and disease. This review discusses the functional role of de novo methyltransferases and in particular DNMT3A1 in the adult brain with special emphasis on synaptic plasticity, memory formation, and brain disorders.
The Epigenetics of Epilepsy and Its Progression Neuroscientist (IF 7.461) Pub Date : 2017-05-04 Rebecca M. Hauser; David C. Henshall; Farah D. Lubin
Epilepsy is a common and devastating neurological disorder characterized by recurrent and unprovoked spontaneous seizures. One leading hypothesis for the development and progression of epilepsy is that large-scale changes in gene transcription and protein expression contribute to aberrant network restructuring and hyperexcitability, resulting in the genesis of repeated seizures. Current research shows that epigenetic mechanisms, including posttranslational alterations to the proteins around which DNA is coiled, chemical modifications to DNA, and the activity of various noncoding RNA molecules exert important influences on these gene networks in experimental epilepsy. Key findings from animal models have been replicated in humans using brain tissue obtained from living patients at the time of neurosurgical resection for pharmacoresistant epilepsy. These findings have spurred efforts to target epigenetic processes to disrupt or modify epilepsy in experimental models with varying degrees of success. In this review, we will (1) summarize the epigenetic mechanisms implicated in epileptogenesis and epilepsy, (2) explore the influence of metabolic factors on epigenetic mechanisms, and (3) assess the potential of using epigenetic markers to support diagnosis and prognosis. Translation of these findings may guide the development of molecular biomarkers and novel therapeutics for prevention or modification of epileptic disorders.
Axonal Regulation of Central Nervous System Myelination: Structure and Function Neuroscientist (IF 7.461) Pub Date : 2017-04-11 Anna Klingseisen; David A. Lyons
Approximately half of the human brain consists of myelinated axons. Central nervous system (CNS) myelin is made by oligodendrocytes and is essential for nervous system formation, health, and function. Once thought simply as a static insulator that facilitated rapid impulse conduction, myelin is now known to be made and remodeled in to adult life. Oligodendrocytes have a remarkable capacity to differentiate by default, but many aspects of their development can be influenced by axons. However, how axons and oligodendrocytes interact and cooperate to regulate myelination in the CNS remains unclear. Here, we review recent advances in our understanding of how such interactions generate the complexity of myelination known to exist in vivo. We highlight intriguing results that indicate that the cross-sectional size of an axon alone may regulate myelination to a surprising degree. We also review new studies, which have highlighted diversity in the myelination of axons of different neuronal subtypes and circuits, and structure-function relationships, which suggest that myelinated axons can be exquisitely fine-tuned to mediate precise conduction needs. We also discuss recent advances in our understanding of how neuronal activity regulates CNS myelination, and aim to provide an integrated overview of how axon-oligodendrocyte interactions sculpt neuronal circuit structure and function.
Olfactory Loss and Regain: Lessons for Neuroplasticity Neuroscientist (IF 7.461) Pub Date : 2017-05-01 Johanna L. Reichert; Veronika Schöpf
For the visual and auditory senses, an array of studies has reported on neuronal reorganization processes after sensory loss. In contrast to this, neuroplasticity has been investigated only scarcely after loss of the olfactory sense. The present review focuses on the current extent of literature on structural and functional neuroplasticity effects after loss, with a focus on magnetic resonance imaging–based studies. We also include findings on the regain of the olfactory sense, for example after successful olfactory training. Existing studies indicate that widespread structural changes beyond the level of the olfactory bulb occur in the brain after loss of the olfactory sense. Moreover, on a functional level, loss of olfactory input not only entails changes in olfaction-related brain regions but also in the trigeminal system. Existing evidence should be strengthened by future longitudinal studies, a more thorough investigation of the neuronal consequences of congenital anosmia, and the application of state-of-the-art neuroimaging methods, such as connectivity analyses and joint analyses of brain structure and function.
GABAergic Transmission during Brain Development: Multiple Effects at Multiple Stages Neuroscientist (IF 7.461) Pub Date : 2017-04-05 Knut Kirmse; Christian A. Hübner; Dirk Isbrandt; Otto W. Witte; Knut Holthoff
In recent years, considerable progress has been achieved in deciphering the cellular and network functions of GABAergic transmission in the intact developing brain. First, in vivo studies in non-mammalian and mammalian species confirmed the long-held assumption that GABA acts as a mainly depolarizing neurotransmitter at early developmental stages. At the same time, GABAergic transmission was shown to spatiotemporally constrain spontaneous cortical activity, whereas firm evidence for GABAergic excitation in vivo is currently missing. Second, there is a growing body of evidence indicating that depolarizing GABA may contribute to the activity-dependent refinement of neural circuits. Third, alterations in GABA actions have been causally linked to developmental brain disorders and identified as potential targets of timed prophylactic interventions. In this article, we review these major recent findings and argue that both depolarizing and inhibitory GABA actions may be crucial for physiological brain maturation.
The Actin Cytoskeleton in SMA and ALS: How Does It Contribute to Motoneuron Degeneration? Neuroscientist (IF 7.461) Pub Date : 2017-05-01 Niko Hensel; Peter Claus
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases with overlapping clinical phenotypes based on impaired motoneuron function. However, the pathomechanisms of both diseases are largely unknown, and it is still unclear whether they converge on the molecular level. SMA is a monogenic disease caused by low levels of functional Survival of Motoneuron (SMN) protein, whereas ALS involves multiple genes as well as environmental factors. Recent evidence argues for involvement of actin regulation as a causative and dysregulated process in both diseases. ALS-causing mutations in the actin-binding protein profilin-1 as well as the ability of the SMN protein to directly bind to profilins argue in favor of a common molecular mechanism involving the actin cytoskeleton. Profilins are major regulat ors of actin-dynamics being involved in multiple neuronal motility and transport processes as well as modulation of synaptic functions that are impaired in models of both motoneuron diseases. In this article, we review the current literature in SMA and ALS research with a focus on the actin cytoskeleton. We propose a common molecular mechanism that explains the degeneration of motoneurons for SMA and some cases of ALS.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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