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Showing papers in "The Neuroscientist in 2017"


Journal ArticleDOI
TL;DR: It is highlighted by highlighting some possible future trends in the further development of weighted small-worldness as part of a deeper and broader understanding of the topology and the functional value of the strong and weak links between areas of mammalian cortex.
Abstract: It is nearly 20 years since the concept of a small-world network was first quantitatively defined, by a combination of high clustering and short path length; and about 10 years since this metric of complex network topology began to be widely applied to analysis of neuroimaging and other neuroscience data as part of the rapid growth of the new field of connectomics. Here, we review briefly the foundational concepts of graph theoretical estimation and generation of small-world networks. We take stock of some of the key developments in the field in the past decade and we consider in some detail the implications of recent studies using high-resolution tract-tracing methods to map the anatomical networks of the macaque and the mouse. In doing so, we draw attention to the important methodological distinction between topological analysis of binary or unweighted graphs, which have provided a popular but simple approach to brain network analysis in the past, and the topology of weighted graphs, which retain more b...

532 citations


Journal ArticleDOI
TL;DR: It is demonstrated that these models can explain the tES behavioral effects as distributed along a continuum from stimulation dependent to network activity dependent, and it is proposed that stochastic resonance is a useful mechanism to explain the general online neuromodulation effects of tES.
Abstract: In recent years, there has been remarkable progress in the understanding and practical use of transcranial electrical stimulation (tES) techniques. Nevertheless, to date, this experimental effort has not been accompanied by substantial reflections on the models and mechanisms that could explain the stimulation effects. Given these premises, the aim of this article is to provide an updated picture of what we know about the theoretical models of tES that have been proposed to date, contextualized in a more specific and unitary framework. We demonstrate that these models can explain the tES behavioral effects as distributed along a continuum from stimulation dependent to network activity dependent. In this framework, we also propose that stochastic resonance is a useful mechanism to explain the general online neuromodulation effects of tES. Moreover, we highlight the aspects that should be considered in future research. We emphasize that tES is not an "easy-to-use" technique; however, it may represent a very fruitful approach if applied within rigorous protocols, with deep knowledge of both the behavioral and cognitive aspects and the more recent advances in the application of stimulation.

318 citations


Journal ArticleDOI
TL;DR: Findings of normal development of functional connectivity networks and their relationships to behaviors and disruptions of the normative functional connectivity development due to identifiable genetic and/or environmental risk factors during the first 2 years of human life are described.
Abstract: Infancy is a critical and immensely important period in human brain development. Subtle changes during this stage may be greatly amplified with the unfolding of different developmental processes, exerting far-reaching consequences. Studies of the structure and behavioral manifestations of the infant brain are fruitful. However, the specific functional brain mechanisms that enable the execution of different behaviors remained elusive until the advent of functional connectivity fMRI (fcMRI), which provides an unprecedented opportunity to probe the infant functional brain development in vivo. Since its inception, a burgeoning field of infant brain functional connectivity study has emerged and thrived during the past decade. In this review, we describe (1) findings of normal development of functional connectivity networks and their relationships to behaviors and (2) disruptions of the normative functional connectivity development due to identifiable genetic and/or environmental risk factors during the first 2 years of human life. Technical considerations of infant fcMRI are also provided. It is our hope to consolidate previous findings so that the field can move forward with a clearer picture toward the ultimate goal of fcMRI-based objective methods for early diagnosis/identification of risks and evaluation of early interventions to optimize developing functional connectivity networks in this critical developmental window.

227 citations


Journal ArticleDOI
TL;DR: In this review, this complexity will be explored across mammalian species, with a focus on social memory, cooperative behaviors, and competitive behaviors.
Abstract: For many, the terms oxytocin and vasopressin immediately evoke images of animals interacting with one another, as both of these neuropeptides have been implicated as being part of the neurochemical "glue" that socially binds animals. However, social environments and social interactions are complex and include behaviors that bring animals together as well as behaviors that keep animals apart. It is at the intersection of social context, social experience, and an individual's sex that oxytocin and vasopressin act to modulate social behavior and social cognition. In this review, this complexity will be explored across mammalian species, with a focus on social memory, cooperative behaviors, and competitive behaviors. Implications for humans as well as future directions will also be considered.

130 citations


Journal ArticleDOI
TL;DR: The general anatomy and physiology of CSF is discussed and reviewed from the perspective of the glymphatic pathway, a discovery which has greatly improved understanding of key factors that control removal of metabolic waste products from the central nervous system in health and disease and identifies an additional purpose for sleep.
Abstract: The overall premise of this review is that cerebrospinal fluid (CSF) is transported within a dedicated peri-vascular network facilitating metabolic waste clearance from the central nervous system while we sleep. The anatomical profile of the network is complex and has been defined as a peri-arterial CSF influx pathway and peri-venous clearance routes, which are functionally coupled by interstitial bulk flow supported by astrocytic aquaporin 4 water channels. The role of the newly discovered system in the brain is equivalent to the lymphatic system present in other body organs and has been termed the "glymphatic pathway" or "(g)lymphatics" because of its dependence on glial cells. We will discuss and review the general anatomy and physiology of CSF from the perspective of the glymphatic pathway, a discovery which has greatly improved our understanding of key factors that control removal of metabolic waste products from the central nervous system in health and disease and identifies an additional purpose for sleep. A brief historical and factual description of CSF production and transport will precede the ensuing discussion of the glymphatic system along with a discussion of its clinical implications.

123 citations


Journal ArticleDOI
TL;DR: This article presents a review of recent advances in neuroscience research in the specific area of brain connectivity as a potential biomarker of Alzheimer’s disease with a focus on the application of graph theory.
Abstract: This article presents a review of recent advances in neuroscience research in the specific area of brain connectivity as a potential biomarker of Alzheimer’s disease with a focus on the application of graph theory. The review will begin with a brief overview of connectivity and graph theory. Then resent advances in connectivity as a biomarker for Alzheimer’s disease will be presented and analyzed.

120 citations


Journal ArticleDOI
TL;DR: This work focuses on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion.
Abstract: The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.

117 citations


Journal ArticleDOI
TL;DR: In vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders are summarized to contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential.
Abstract: Since the development of transcranial magnetic stimulation (TMS) in the early 1980s, a range of repetitive TMS (rTMS) protocols are now available to modulate neuronal plasticity in clinical and non-clinical populations. However, despite the wide application of rTMS in humans, the mechanisms underlying rTMS-induced plasticity remain uncertain. Animal and in vitro models provide an adjunct method of investigating potential synaptic and non-synaptic mechanisms of rTMS-induced plasticity. This review summarizes in vitro experimental studies, in vivo studies with intact rodents, and preclinical models of selected neurological disorders-Parkinson's disease, depression, and stroke. We suggest that these basic research findings can contribute to the understanding of how rTMS-induced plasticity can be modulated, including novel mechanisms such as neuroprotection and neurogenesis that have significant therapeutic potential.

112 citations


Journal ArticleDOI
TL;DR: This review revisits the single-cell electrophysiological evidence for a nociceptive neural code and considers how those findings relate to recent advances in understanding systems-level dynamic processes that suggest the existence of a “dynamic pain connectome” as a spatiotemporal physiological signature of pain.
Abstract: Pain occurs in time. In naturalistic settings, pain perception is sometimes stable but often varies in intensity and quality over the course of seconds, minutes, and days. A principal aim in classic electrophysiology studies of pain was to uncover a neural code based on the temporal patterns of single neuron firing. In contrast, modern neuroimaging studies have placed emphasis on uncovering the spatial pattern of brain activity (or “map”) that may reflect the pain experience. However, in the emerging field of connectomics, communication within and among brain networks is characterized as intrinsically dynamic on multiple time scales. In this review, we revisit the single-cell electrophysiological evidence for a nociceptive neural code and consider how those findings relate to recent advances in understanding systems-level dynamic processes that suggest the existence of a “dynamic pain connectome” as a spatiotemporal physiological signature of pain. We explore how spontaneous activity fluctuations in this ...

98 citations


Journal ArticleDOI
TL;DR: The mounting evidence indicating that mirroring others’ actions engages a broad system of reciprocally connected cortical areas, which extends well beyond the classical IPL-PMv circuit and might even include subcortical regions such as the basal ganglia is highlighted.
Abstract: Mirror neurons (MNs) are a fascinating class of cells originally discovered in the ventral premotor cortex (PMv) and, subsequently, in the inferior parietal lobule (IPL) of the macaque, which become active during both the execution and observation of actions. In this review, I will first highlight the mounting evidence indicating that mirroring others' actions engages a broad system of reciprocally connected cortical areas, which extends well beyond the classical IPL-PMv circuit and might even include subcortical regions such as the basal ganglia. Then, I will present the most recent findings supporting the idea that the observation of one's own actions, which might play a role in the ontogenetic origin and tuning of MNs, retains a particular relevance within the adult MN system. Finally, I will propose that both cortical and subcortical mechanisms do exist to decouple MN activity from the motor output, in order to render it exploitable for high-order perceptual, cognitive, and even social functions. The findings reviewed here provide an original framework for envisaging the main challenges and experimental directions of future neurophysiological and neuroanatomical studies of the monkey MN system.

83 citations


Journal ArticleDOI
TL;DR: The perspective of neuro inflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders, with emphasis on mast cell-glia interactions.
Abstract: The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions.

Journal ArticleDOI
TL;DR: The versatile role of Wnt/β-catenin signaling during neural development is summarized, some recent studies linking Wnt signaling to neurological disorders are discussed and new therapeutic strategies for neurological diseases are discussed.
Abstract: Wnt/β-catenin signaling plays a crucial role throughout all stages of brain development and remains important in the adult brain. Accordingly, many neurological disorders have been linked to Wnt signaling. Defects in Wnt signaling during neural development can give rise to birth defects or lead to neurological dysfunction later in life. Developmental signaling events can also be hijacked in the adult and result in disease. Moreover, knowledge about the physiological role of Wnt signaling in the brain might lead to new therapeutic strategies for neurological diseases. Especially, the important role for Wnt signaling in neural differentiation of pluripotent stem cells has received much attention as this might provide a cure for neurodegenerative disorders. In this review, we summarize the versatile role of Wnt/β-catenin signaling during neural development and discuss some recent studies linking Wnt signaling to neurological disorders.

Journal ArticleDOI
TL;DR: The role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophine 4 (NT4) and their respective proform in cellular processes related to learning and memory is explored.
Abstract: Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.

Journal ArticleDOI
Henry H. Yin1
TL;DR: A new conceptual framework is introduced for understanding the role of the BG in behavior and provides a solution to the posture/movement problem, by postulating that BG outputs send descending signals to alter the reference states of downstream position control systems for orientation and body configuration.
Abstract: The basal ganglia (BG) are the major subcortical nuclei in the brain. Disorders implicating the BG are characterized by diverse symptoms, but it remains unclear what these symptoms have in common or how they can be explained by changes in the BG circuits. This review summarizes recent findings that not only question traditional assumptions about the role of the BG in movement but also elucidate general computations performed by these circuits. To explain these findings, a new conceptual framework is introduced for understanding the role of the BG in behavior. According to this framework, the cortico-BG networks implement transition control in an extended hierarchy of closed loop negative feedback control systems. The transition control model provides a solution to the posture/movement problem, by postulating that BG outputs send descending signals to alter the reference states of downstream position control systems for orientation and body configuration. It also explains major neurological symptoms associated with BG pathology as a result of changes in system parameters such as multiplicative gain and damping.

Journal ArticleDOI
TL;DR: This work reviews studies of music training that employ a biological approach to reveal the integrity of sound processing in the brain, the bearing these mechanisms have on everyday communication, and how these processes are shaped by experience.
Abstract: Sound is an invisible but powerful force that is central to everyday life. Studies in the neurobiology of everyday communication seek to elucidate the neural mechanisms underlying sound processing, their stability, their plasticity, and their links to language abilities and disabilities. This sound processing lies at the nexus of cognitive, sensorimotor, and reward networks. Music provides a powerful experimental model to understand these biological foundations of communication, especially with regard to auditory learning. We review studies of music training that employ a biological approach to reveal the integrity of sound processing in the brain, the bearing these mechanisms have on everyday communication, and how these processes are shaped by experience. Together, these experiments illustrate that music works in synergistic partnerships with language skills and the ability to make sense of speech in complex, everyday listening environments. The active, repeated engagement with sound demanded by music making augments the neural processing of speech, eventually cascading to listening and language. This generalization from music to everyday communications illustrates both that these auditory brain mechanisms have a profound potential for plasticity and that sound processing is biologically intertwined with listening and language skills. A new wave of studies has pushed neuroscience beyond the traditional laboratory by revealing the effects of community music training in underserved populations. These community-based studies reinforce laboratory work highlight how the auditory system achieves a remarkable balance between stability and flexibility in processing speech. Moreover, these community studies have the potential to inform health care, education, and social policy by lending a neurobiological perspective to their efficacy.

Journal ArticleDOI
TL;DR: This review discusses recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterized localization to the synapse, and describes how the regulation of synapse physiology by tau and its phosphorylation may inform the understanding of tAUopathies and comorbid diseases.
Abstract: Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past 30 years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review discusses recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterized localization to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signaling role. We also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and comorbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.

Journal ArticleDOI
TL;DR: This article discusses research that embraces a distributed view of emotion circuits and efforts to unravel the impact on emotional manipulations on the processing of several large-scale brain networks that are chiefly important for mental operations traditionally labeled with terms such as “perception,’ “action,” and “cognition.”
Abstract: Research on the emotional brain has often focused on a few structures thought to be central to this type of processing-hypothalamus, amygdala, insula, and so on Conceptual thinking about emotion has viewed this mental faculty as linked to broader brain circuits, too, including early ideas by Papez and others In this article, we discuss research that embraces a distributed view of emotion circuits and efforts to unravel the impact on emotional manipulations on the processing of several large-scale brain networks that are chiefly important for mental operations traditionally labeled with terms such as "perception," "action," and "cognition" Furthermore, we describe networks as dynamic processes and how emotion-laden stimuli strongly affect network structure As networks are not static entities, their organization unfolds temporally, such that specific brain regions affiliate with them in a time-varying fashion Thus, at a specific moment, brain regions participate more strongly in some networks than others In this dynamic view of brain function, emotion has broad, distributed effects on processing in a manner that transcends traditional boundaries and inflexible labels, such as "emotion" and "cognition" What matters is the coordinated action that supports behaviors

Journal ArticleDOI
TL;DR: This review describes DA signaling in the amygdala, and DA regulation of synaptic transmission and synaptic plasticity of the amygdala neurons, and discusses a potential contribution of DA-related mechanisms to the pathogenesis of posttraumatic stress disorder.
Abstract: In addition to modulating a number of cognitive functions including reward, punishment, motivation, and salience, dopamine (DA) plays a pivotal role in regulating threat-related emotional memory. Changes in neural circuits of the amygdala nuclei are also critically involved in the acquisition and expression of emotional memory. In this review, we summarize the regulation of amygdala circuits by DA. Specifically, we describe DA signaling in the amygdala, and DA regulation of synaptic transmission and synaptic plasticity of the amygdala neurons. Finally, we discuss a potential contribution of DA-related mechanisms to the pathogenesis of posttraumatic stress disorder.

Journal ArticleDOI
TL;DR: The general pathways that convey ascending sensory and descending motor information are reviewed, using the rodent whisker system as a model to take advantage of the cell type specificity possible in this model and a brief description of changes in these circuits during motor learning is described.
Abstract: Scientists and philosophers have long appreciated that active somatosensation requires the sensory and motor systems to exchange information about body the body's movements as well as touch in order to accurately interpret incoming somatosensory information and plan future movements. However, the circuitry underlying this sensory and motor integration is complicated and is difficult to study without tools to label specific cellular components in the various brain regions involved. Here, I review the general pathways that convey ascending sensory and descending motor information, using the rodent whisker system as a model to take advantage of the cell type specificity possible in this model. I then detail the circuits in motor cortex in which incoming information from somatosensory cortex and thalamus is integrated. I close with a brief description of changes in these circuits during motor learning.

Journal ArticleDOI
Stefanie Robel1
TL;DR: The currently available evidence suggests that epilepsy is not a disease of neurons alone, but that astrocytes, glial cells in the brain, can be major contributors to the disease, especially when they adopt a reactive state in response to central nervous system insult.
Abstract: Epilepsy is among the most prevalent chronic neurological diseases and affects an estimated 2.2 million people in the United States alone. About one third of patients are resistant to currently available antiepileptic drugs, which are exclusively targeting neuronal function. Yet, reactive astrocytes have emerged as potential contributors to neuronal hyperexcitability and seizures. Astrocytes react to any kind of CNS insult with a range of cellular adjustments to form a scar and protect uninjured brain regions. This process changes astrocyte physiology and can affect neuronal network function in various ways. Traumatic brain injury and stroke, both conditions that trigger astroglial scar formation, are leading causes of acquired epilepsies and surgical removal of this glial scar in patients with drug-resistant epilepsy can alleviate the seizures. This review will summarize the currently available evidence suggesting that epilepsy is not a disease of neurons alone, but that astrocytes, glial cells in the brain, can be major contributors to the disease, especially when they adopt a reactive state in response to central nervous system insult.

Journal ArticleDOI
TL;DR: Evidence that the two major calpain isoforms in the brain play opposite functions in synaptic plasticity is provided, which has important implications for the understanding of learning and memory and disorders associated with impairment in these processes.
Abstract: Although calpain was proposed to participate in synaptic plasticity and learning and memory more than 30 years ago, the mechanisms underlying its activation and the roles of different substrates have remained elusive. Recent findings have provided evidence that the two major calpain isoforms in the brain, calpain-1 and calpain-2, play opposite functions in synaptic plasticity. In particular, while calpain-1 activation is the initial trigger for certain forms of synaptic plasticity, that is, long-term potentiation, calpain-2 activation restricts the extent of plasticity. Moreover, while calpain-1 rapidly cleaves regulatory and cytoskeletal proteins, calpain-2-mediated stimulation of local protein synthesis reestablishes protein homeostasis. These findings have important implications for our understanding of learning and memory and disorders associated with impairment in these processes.

Journal ArticleDOI
TL;DR: The residual abilities and neural activity that have been described in blindsight are discussed and the implications for understanding the intact system are discussed.
Abstract: Damage to the primary visual cortex removes the major input from the eyes to the brain, causing significant visual loss as patients are unable to perceive the side of the world contralateral to the damage. Some patients, however, retain the ability to detect visual information within this blind region; this is known as blindsight. By studying the visual pathways that underlie this residual vision in patients, we can uncover additional aspects of the human visual system that likely contribute to normal visual function but cannot be revealed under physiological conditions. In this review, we discuss the residual abilities and neural activity that have been described in blindsight and the implications of these findings for understanding the intact system.

Journal ArticleDOI
TL;DR: Potential therapeutic strategies for myelin repair are provided by analyzing the relevance between the pathological changes and the regulatory roles of CXCL12/CXCR4/C XCR7 during MS.
Abstract: The chemokine CXCL12 plays a vital role in regulating the development of the central nervous system (CNS) by binding to its receptors CXCR4 and CXCR7. Recent studies reported that the CXCL12/CXCR4/CXCR7 axis regulates both embryonic and adult oligodendrocyte precursor cells (OPCs) in their proliferation, migration, and differentiation. The changes in the expression and distribution of CXCL12 and its receptors are tightly associated with the pathological process of demyelination in multiple sclerosis (MS), suggesting that modulating the CXCL12/CXCR4/CXCR7 axis may benefit myelin repair by enhancing OPC recruitment and differentiation. This review aims to integrate the current findings of the CXCL12/CXCR4/CXCR7 signaling pathway in the CNS and to highlight its role in oligodendrocyte development and demyelinating diseases. Furthermore, this review provides potential therapeutic strategies for myelin repair by analyzing the relevance between the pathological changes and the regulatory roles of CXCL12/CXCR4/CXCR7 during MS.

Journal ArticleDOI
TL;DR: The literature is reviewed and discussed on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.
Abstract: Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson's disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of α-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, α- and β-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology.

Journal ArticleDOI
TL;DR: Insight is provided into addressing the translational gap, the design of relevant preclinical experiments are guided, and development of new approaches for motor recovery in patients with complete SCIs are facilitated.
Abstract: Significant advancements in spinal epidural stimulation (ES) strategies to enable volitional motor control in persons with a complete spinal cord injury (SCI) have generated much excitement in the field of neurorehabilitation. Still, an obvious gap lies in the ability of ES to effectively generate a robust locomotor stepping response after a complete SCI in rodents, but not in humans. In order to reveal potential discrepancies between rodent and human studies that account for this void, in this review, we summarize the findings of studies that have utilized ES strategies to enable successful hindlimb stepping in spinal rats. Recent clinical and preclinical evidence indicates that motor training with ES plays a crucial role in tuning spinal neural circuitry to generate meaningful motor output. Concurrently administered pharmacology can also facilitate the circuitry to provide near optimal motor performance in SCI rats. However, as of today, the evidence for pharmacological agents to enhance motor function in persons with complete SCI is insignificant. These and other recent findings discussed in this review provide insight into addressing the translational gap, guide the design of relevant preclinical experiments, and facilitate development of new approaches for motor recovery in patients with complete SCIs.

Journal ArticleDOI
TL;DR: This review has summarized the effects of inflammation on NSCs in relation to their origin and briefly described the NSC activity during different neurological diseases or experimental models.
Abstract: Neural stem/progenitor cells (NSCs/NPCs) are present in different locations in the central nervous system. In the subgranular zone (SGZ) there is a constant generation of new neurons under normal conditions. New neurons are also formed from the subventricular zone (SVZ) NSCs, and they migrate anteriorly as neuroblast to the olfactory bulb in rodents, whereas in humans migration is directed toward striatum. Most CNS injuries elicit proliferation and migration of the NSCs toward the injury site, indicating the activation of a regenerative response. However, regeneration from NSC is incomplete, and this could be due to detrimental cues encountered during inflammation. Different CNS diseases and trauma cause activation of the innate and adaptive immune responses that influence the NSCs. Furthermore, NSCs in the brain react differently to inflammatory cues than their counterparts in the spinal cord. In this review, we have summarized the effects of inflammation on NSCs in relation to their origin and briefly described the NSC activity during different neurological diseases or experimental models.

Journal ArticleDOI
TL;DR: It is proposed that conceptually all sensory information in real time provided to the brain and spinal cord can be viewed as a feed-forward phenomenon and that the spinal cord continually adapts to a broad array of ongoing sensory information that is used to adjust the probability of making timely and predictable decisions of selected networks that will execute a given response.
Abstract: We present a new perspective on the concept of feed-forward compared to feedback mechanisms for motor control. We propose that conceptually all sensory information in real time provided to the brai...

Journal ArticleDOI
TL;DR: After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind-body crosstalk.
Abstract: Sleep and its disorders are known to affect the functions of essential organs and systems in the body. However, very little is known about how the blood-brain barrier (BBB) is regulated. A few years ago, we launched a project to determine the impact of sleep fragmentation and chronic sleep restriction on BBB functions, including permeability to fluorescent tracers, tight junction protein expression and distribution, glucose and other solute transporter activities, and mediation of cellular mechanisms. Recent publications and relevant literature allow us to summarize here the sleep-BBB interactions in five sections: (1) the structural basis enabling the BBB to serve as a huge regulatory interface; (2) BBB transport and permeation of substances participating in sleep-wake regulation; (3) the circadian rhythm of BBB function; (4) the effect of experimental sleep disruption maneuvers on BBB activities, including regional heterogeneity, possible threshold effect, and reversibility; and (5) implications of sleep disruption-induced BBB dysfunction in neurodegeneration and CNS autoimmune diseases. After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind-body crosstalk. The pharmaceutical industry should take into consideration that sleep disruption alters the pharmacokinetics of BBB permeation and CNS drug delivery, being attentive to the chrono timing and activation of co-transporters in subjects with sleep disorders.

Journal ArticleDOI
TL;DR: The axon initial segment (AIS) is a key neuronal compartment because it is responsible for action potential initiation and plasticity plays important roles in physiological functions as diverse as memory formation, hearing, and motor control.
Abstract: The axon initial segment (AIS) is a key neuronal compartment because it is responsible for action potential initiation. The local density of Na+ channels, the biophysical properties of K+ channels, as well as the length and diameter of the AIS determine the spiking of neurons. These parameters undergo important modifications during development. The development of the AIS is governed by intrinsic mechanisms. In addition, surrounding neuronal networks modify its maturation. As a result, neurons get tuned to particular physiological functions. Neuronal activity also influences the morphology of the mature AIS. When excitatory neurons are hyperactive, their AIS undergo structural changes that decrease their excitability and thereby maintain the activity within a given range. These slow homeostatic regulatory mechanisms occur on a time scale of hours or days. In contrast, the activation of metabotropic receptors modulates the properties of ion channels expressed at the AIS within seconds and consequently produces fast adjustments of neuronal excitability. Recent results suggest that this plasticity plays important roles in physiological functions as diverse as memory formation, hearing, and motor control.

Journal ArticleDOI
TL;DR: This article reviews the pathohistology of cerebral concussions and examines the extant literature with a focus on electrophysiological and neuroimaging findings, particularly as they are related to chronic traumatic encephalopathy.
Abstract: Little is known of the long-term effects of sports-related concussion. Within the scientific literature, conclusions vary substantially where some work suggests there are no long-term consequences at all and other studies show rampant neurodegeneration thought to be caused by sometimes even a single concussive blow to the head. There is growing evidence that supports multiple long-term outcomes, showing both subclinical and clinically relevant changes in the brains of athletes, young and old alike. This article reviews the pathohistology of cerebral concussions and examines the extant literature with a focus on electrophysiological and neuroimaging findings. Neurobehavioral and neurocognitive changes are also reviewed, particularly as they are related to chronic traumatic encephalopathy. Lacunae within the literature are explored, and future research directions are proposed.