Showing papers in "The Neuroscientist in 2016"

Mechanism of Deep Brain Stimulation: Inhibition, Excitation, or Disruption?

Abstract: Deep brain stimulation (DBS), applying high-frequency electrical stimulation to deep brain structures, has now provided an effective therapeutic option for treatment of various neurological and psychiatric disorders. DBS targeting the internal segment of the globus pallidus, subthalamic nucleus, and thalamus is used to treat symptoms of movement disorders, such as Parkinson’s disease, dystonia, and tremor. However, the mechanism underlying the beneficial effects of DBS remains poorly understood and is still under debate: Does DBS inhibit or excite local neuronal elements? In this short review, we would like to introduce our recent work on the physiological mechanism of DBS and propose an alternative explanation: DBS dissociates input and output signals, resulting in the disruption of abnormal information flow through the stimulation site.

Epigenetic Basis of Mental Illness

Abstract: Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses. Exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. Here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. We review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. While epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions.

Transcranial Magnetic Stimulation Decomposing the Processes Underlying Action Preparation

Abstract: Preparing actions requires the operation of several cognitive control processes that influence the state of the motor system to ensure that the appropriate behavior is ultimately selected and executed. For example, some form of competition resolution ensures that the right action is chosen among alternatives, often in the presence of conflict; at the same time, impulse control ought to be deployed to prevent premature responses. Here we review how state-changes in the human motor system during action preparation can be studied through motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the contralateral primary motor cortex (M1). We discuss how the physiological fingerprints afforded by MEPs have helped to decompose some of the dynamic and effector-specific influences on the motor system during action preparation. We focus on competition resolution, conflict and impulse control, as well as on the influence of higher cognitive decision-related variables. The selected examples demonstrate the usefulness of MEPs as physiological readouts for decomposing the influence of distinct, but often overlapping, control processes on the human motor system during action preparation.

Regional Homogeneity A Multimodal, Multiscale Neuroimaging Marker of the Human Connectome

Abstract: Much effort has been made to understand the organizational principles of human brain function using functional magnetic resonance imaging (fMRI) methods, among which resting-state fMRI (rfMRI) is an increasingly recognized technique for measuring the intrinsic dynamics of the human brain. Functional connectivity (FC) with rfMRI is the most widely used method to describe remote or long-distance relationships in studies of cerebral cortex parcellation, interindividual variability, and brain disorders. In contrast, local or short-distance functional interactions, especially at a scale of millimeters, have rarely been investigated or systematically reviewed like remote FC, although some local FC algorithms have been developed and applied to the discovery of brain-based changes under neuropsychiatric conditions. To fill this gap between remote and local FC studies, this review will (1) briefly survey the history of studies on organizational principles of human brain function; (2) propose local functional homogeneity as a network centrality to characterize multimodal local features of the brain connectome; (3) render a neurobiological perspective on local functional homogeneity by linking its temporal, spatial, and individual variability to information processing, anatomical morphology, and brain development; and (4) discuss its role in performing connectome-wide association studies and identify relevant challenges, and recommend its use in future brain connectomics studies.

Cerebellar Transcranial Direct Current Stimulation (ctDCS) A Novel Approach to Understanding Cerebellar Function in Health and Disease

Abstract: The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions.

The Next Step A Common Neural Mechanism for Freezing of Gait

Abstract: Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal cessation of normal footsteps while walking. Despite a great deal of empirical research, the pathophysiological mechanisms underlying the symptom remain unclear. In this targeted review, we synthesize recent insights from research into freezing in an effort to clarify the neurobiological basis of this phenomenon. We conclude that freezing manifests via a common neural pathway in which transient increases in inhibitory basal ganglia output lead to decreased activity within the brainstem structures that coordinate gait. This cascade may be triggered through dopaminergic depletion in the striatum and over-activity within the subthalamic nucleus. These insights may benefit both the diagnostic and therapeutic management of freezing in Parkinson's disease.

How Has the Internet Reshaped Human Cognition

Abstract: Throughout our evolutionary history, our cognitive systems have been altered by the advent of technological inventions such as primitive tools, spoken language, writing, and arithmetic systems. Thirty years ago, the Internet surfaced as the latest technological invention poised to deeply reshape human cognition. With its multifaceted affordances, the Internet environment has profoundly transformed our thoughts and behaviors. Growing up with Internet technologies, "Digital Natives" gravitate toward "shallow" information processing behaviors characterized by rapid attention shifting and reduced deliberations. They engage in increased multitasking behaviors that are linked to increased distractibility and poor executive control abilities. Digital natives also exhibit higher prevalence of Internet-related addictive behaviors that reflect altered reward-processing and self-control mechanisms. Recent neuroimaging investigations have suggested associations between these Internet-related cognitive impacts and structural changes in the brain. Against mounting apprehension over the Internet's consequences on our cognitive systems, several researchers have lamented that these concerns were often exaggerated beyond existing scientific evidence. In the present review, we aim to provide an objective overview of the Internet's impacts on our cognitive systems. We critically discuss current empirical evidence about how the Internet environment has altered the cognitive behaviors and structures involved in information processing, executive control, and reward-processing.

How Schwann Cells Sort Axons New Concepts

Abstract: Peripheral nerves contain large myelinated and small unmyelinated (Remak) fibers that perform different functions. The choice to myelinate or not is dictated to Schwann cells by the axon itself, based on the amount of neuregulin I-type III exposed on its membrane. Peripheral axons are more important in determining the final myelination fate than central axons, and the implications for this difference in Schwann cells and oligodendrocytes are discussed. Interestingly, this choice is reversible during pathology, accounting for the remarkable plasticity of Schwann cells, and contributing to the regenerative potential of the peripheral nervous system. Radial sorting is the process by which Schwann cells choose larger axons to myelinate during development. This crucial morphogenetic step is a prerequisite for myelination and for differentiation of Remak fibers, and is arrested in human diseases due to mutations in genes coding for extracellular matrix and linkage molecules. In this review we will summarize progresses made in the last years by a flurry of reverse genetic experiments in mice and fish. This work revealed novel molecules that control radial sorting, and contributed unexpected ideas to our understanding of the cellular and molecular mechanisms that control radial sorting of axons.

The Parkinson Disease Mitochondrial Hypothesis Where Are We at

Abstract: Parkinson's disease is a common, adult-onset neurodegenerative disorder whose pathogenesis is still under intense investigation. Substantial evidence from postmortem human brain tissue, genetic- and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of the disease. This review discusses our current understanding of Parkinson's disease-related mitochondrial dysfunction, including bioenergetic defects, mitochondrial DNA alterations, altered mitochondrial dynamics, activation of mitochondrial-dependent programmed cell death, and perturbations in mitochondrial tethering to the endoplasmic reticulum. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of neurodegeneration in Parkinson's disease.

The Insula A “Hub of Activity” in Migraine

Abstract: The insula, a “cortical hub” buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new poten...

Brain Neuromodulation Techniques A Review

Abstract: The modulation of brain function via the application of weak direct current was first observed directly in the early 19th century. In the past 3 decades, transcranial magnetic stimulation and deep brain stimulation have undergone clinical translation, offering alternatives to pharmacological treatment of neurological and neuropsychiatric disorders. Further development of novel neuromodulation techniques employing ultrasound, micro-scale magnetic fields and optogenetics is being propelled by a rapidly improving understanding of the clinical and experimental applications of artificially stimulating or depressing brain activity in human health and disease. With the current rapid growth in neuromodulation technologies and applications, it is timely to review the genesis of the field and the current state of the art in this area.

Scenes, Spaces, and Memory Traces What Does the Hippocampus Do?

Abstract: The hippocampus is one of the most closely scrutinized brain structures in neuroscience. While traditionally associated with memory and spatial cognition, in more recent years it has also been linked with other functions, including aspects of perception and imagining fictitious and future scenes. Efforts continue apace to understand how the hippocampus plays such an apparently wide-ranging role. Here we consider recent developments in the field and in particular studies of patients with bilateral hippocampal damage. We outline some key findings, how they have subsequently been challenged, and consider how to reconcile the disparities that are at the heart of current lively debates in the hippocampal literature.

Serotonin 1A and Serotonin 4 Receptors Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants

Abstract: Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants. There is a growing body of evidence supporting critical roles of 5-HT1A and 5-HT4 receptor subtypes in mediating successful depression treatments. In addition, appropriate activation of these receptors may be associated with a faster onset of the therapeutic response. This review will examine the known roles of 5-HT1A and 5-HT4 receptors in mediating both the pathophysiology of depression and anxiety and the treatment of these mood disorders. At the end of the review, the role of these receptors in the regulation of adult hippocampal neurogenesis will also be discussed. Ultimately, we propose that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders.

ThermoTRPs and Pain

Abstract: The ability of the body to perceive noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors. The molecular receptors of noxious mechanical, temperature, or chemical stimuli are expressed in these neurons and have drawn considerable attention as possible targets for analgesic development to improve treatment for the millions who suffer from chronic pain conditions. A number of thermoTRPs, a subset of the transient receptor potential family of ion channels, are activated by a wide range on noxious stimuli. In this review, we review the function of these channels and examine the evidence that thermoTRPs play a vital role in acute, inflammatory and neuropathic nociception.

A Place at the Table LTD as a Mediator of Memory Genesis

Abstract: Resolving how our brains encode information requires an understanding of the cellular processes taking place during memory formation. Since the 1970s, considerable effort has focused on determining the properties and mechanisms underlying long-term potentiation (LTP) at glutamatergic synapses and how these processes influence initiation of new memories. However, accumulating evidence suggests that long-term depression (LTD) of synaptic strength, particularly at glutamatergic synapses, is a bona fide learning and memory mechanism in the mammalian brain. The known range of mechanisms capable of inducing LTD has been extended to those including NMDAR-independent forms, neuromodulator-dependent LTD, synaptic depression following stress, and non-synaptically induced forms. The examples of LTD observed at the hippocampal CA1 synapse to date demonstrate features consistent with LTP, including homo- and heterosynaptic expression, extended duration beyond induction (several hours to weeks), and association with encoding of distinct types of memories. Canonical mechanisms through which synapses undergo LTD include activation of phosphatases, initiation of protein synthesis, and dynamic regulation of presynaptic glutamate release and/or postsynaptic glutamate receptor endocytosis. Here, we will discuss the pre- and postsynaptic changes underlying LTD, recent advances in the identification and characterization of novel mechanisms underlying LTD, and how engagement of these processes constitutes a cellular analog for the genesis of specific types of memories.

Injury-Induced Neurogenesis Mechanisms and Relevance

Abstract: Partial recovery from brain injury due to trauma, hypoxia, or stroke, is ubiquitous and occurs largely through unknown mechanisms. It is now well accepted that injury enhances proliferation of quiescent stem and progenitor cells in specialized niches within the brain. However, whether this injury-induced neurogenesis contributes to recovery after brain injury remains controversial. Recent evidence suggests that hippocampal neural stem/precursor cell activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following brain injury from a variety of causes. However, other aspects of injury-induced neurogenesis, including its contribution to adverse sequelae such as seizures, are still being investigated. The purpose of this review is to provide an overview of adult hippocampal neurogenesis and how it relates to injury and explain how current mouse technology is allowing for better understanding of whether manipulating this natural process might eventually help inform therapy following brain injury.

24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival:

Abstract: The major cholesterol metabolite in brain, 24(S)-hydroxycholesterol (24S-HC), serves as a vehicle for cholesterol removal. Its effects on neuronal function, however, have only recently begun to be investigated. Here, we review that nascent work. Our own studies have demonstrated that 24S-HC has potent positive modulatory effects on N-methyl-d-aspartate (NMDA) receptor (NMDAR) function. This could have implications not only for brain plasticity but also for pathological NMDAR overuse. Other work has demonstrated effects of 24S-HC on neuronal survival and as a possible biomarker of neurodegenerative disease. Depending on circumstances, both upregulation/mimicry of 24S-HC signaling and down-regulation/antagonism may have therapeutic potential. We are interested in the possibility that synthetic analogues of 24S-HC with positive effects at NMDARs may hold neurotherapeutic promise, given the role of NMDA receptor hypofunction in certain neuropsychiatric disorders.

Relearning to See in Cortical Blindness

Abstract: The incidence of cortically induced blindness is increasing as our population ages. The major cause of cortically induced blindness is stroke affecting the primary visual cortex. While the impact of this form of vision loss is devastating to quality of life, the development of principled, effective rehabilitation strategies for this condition lags far behind those used to treat motor stroke victims. Here we summarize recent developments in the still emerging field of visual restitution therapy, and compare the relative effectiveness of different approaches. We also draw insights into the properties of recovered vision, its limitations and likely neural substrates. We hope that these insights will guide future research and bring us closer to the goal of providing much-needed rehabilitation solutions for this patient population.

Acupuncture-Induced Analgesia A Neurobiological Basis in Purinergic Signaling

Abstract: Chronic pain is a debilitating and rather common health problem. The present shortage in analgesic drugs with a favorable spectrum but without remarkable side effects furthered the search for alternative therapeutic manipulations. Increasing evidence from both basic and clinical research on acupuncture, a main alternative therapy of traditional Chinese medicine, suggests that chronic pain is sensitive to acupuncture procedures. Clarification of the underlying mechanisms is a challenge of great theoretical and practical significance. The seminal hypothesis of Geoffrey Burnstock and the astounding findings of Maiken Nedergaard on the involvement of purinergic signaling in the beneficial effects of acupuncture fertilized the field and led to an intensification of research on acupurines. In this review, we will summarize the state-of-the-art situation and try to forecast how the field is likely to develop in the future.

Androgen Modulation of Hippocampal Structure and Function

Abstract: Androgens have profound effects on hippocampal structure and function, including induction of spines and spine synapses on the dendrites of CA1 pyramidal neurons, as well as alterations in long-term synaptic plasticity (LTP) and hippocampally dependent cognitive behaviors. How these effects occur remains largely unknown. Emerging evidence, however, suggests that one of the key elements in the response mechanism may be modulation of brain-derived neurotrophic factor (BDNF) in the mossy fiber (MF) system. In male rats, orchidectomy increases synaptic transmission and excitability in the MF pathway. Testosterone reverses these effects, suggesting that testosterone exerts tonic suppression on MF BDNF levels. These findings suggest that changes in hippocampal function resulting from declining androgen levels may reflect the outcome of responses mediated through normally balanced, but opposing, mechanisms: loss of androgen effects on the hippocampal circuitry may be compensated, at least in part, by an increase in BDNF-dependent MF plasticity.

Hippocampal Wnt Signaling: Memory Regulation and Hormone Interactions

Abstract: Wnt signaling has emerged in recent years as a major player in both nervous system development and adult synaptic plasticity. Of particular relevance to researchers studying learning and memory, Wnt signaling is critical for normal functioning of the hippocampus, a brain region that is essential for many types of memory formation and whose dysfunction is implicated in numerous neurodegenerative and psychiatric conditions. Impaired hippocampal Wnt signaling is implicated in several of these conditions, however, little is known about how Wnt signaling mediates hippocampal memory formation. This review will provide a general overview of Wnt signaling and discuss evidence demonstrating a key role for Wnt signaling in hippocampal memory formation in both normal and disease states. The regulation of Wnt signaling by ovarian sex steroid hormones will also be highlighted, given that the neuroprotection afforded by Wnt-hormone interactions may have significant implications for cognitive function in aging, neurodegenerative disease, and ischemic injury.

Deep Brain Stimulation More Complex than the Inhibition of Cells and Excitation of Fibers

Abstract: High-frequency deep brain stimulation (DBS) is an effective treatment for some movement disorders. Though mechanisms underlying DBS are still unclear, commonly accepted theories include a “functional inhibition” of neuronal cell bodies and the excitation of axonal projections near the electrodes. It is becoming clear, however, that the paradoxical dissociation “local inhibition” and “distant excitation” is far more complex than initially thought. Despite an initial increase in neuronal activity following stimulation, cells are often unable to maintain normal ionic concentrations, particularly those of sodium and potassium. Based on currently available evidence, we proposed an alternative hypothesis. Increased extracellular concentrations of potassium during DBS may change the dynamics of both cells and axons, contributing not only to the intermittent excitation and inhibition of these elements but also to interrupt abnormal pathological activity. In this article, we review mechanisms through which high ex...

Mitochondria Major Regulators of Neural Development

Abstract: Mitochondria are organelles derived from primitive symbiosis between archeon ancestors and prokaryotic α-proteobacteria species, which lost the capacity of synthetizing most proteins encoded the bacterial DNA, along the evolutionary process of eukaryotes. Nowadays, mitochondria are constituted by small circular mitochondrial DNA of 16 kb, responsible for the control of several proteins, including polypeptides of the electron transport chain. Throughout evolution, these organelles acquired the capacity of regulating energy production and metabolism, thus becoming central modulators of cell fate. In fact, mitochondria are crucial for a variety of cellular processes, including adenosine triphosphate production by oxidative phosphorylation, intracellular Ca(2+) homeostasis, generation of reactive oxygen species, and also cellular specialization in a variety of tissues that ultimately relies on specific mitochondrial specialization and maturation. In this review, we discuss recent evidence extending the importance of mitochondrial function and energy metabolism to the context of neuronal development and adult neurogenesis.

The KCC2 Cotransporter and Human Epilepsy Getting Excited About Inhibition

Abstract: The cation-Cl- cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl- extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed "epilepsy of infancy with migrating focal seizures" (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl- extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders.

Arbitration between Action Strategies in Obsessive-Compulsive Disorder.

Abstract: Decision making in a complex world, characterized both by predictable regularities and by frequent departures from the norm, requires dynamic switching between rapid habit-like, automatic processes and slower, more flexible evaluative processes. These strategies, formalized as "model-free" and "model-based" reinforcement learning algorithms, respectively, can lead to divergent behavioral outcomes, requiring a mechanism to arbitrate between them in a context-appropriate manner. Recent data suggest that individuals with obsessive-compulsive disorder (OCD) rely excessively on inflexible habit-like decision making during reinforcement-driven learning. We propose that inflexible reliance on habit in OCD may reflect a functional weakness in the mechanism for context-appropriate dynamic arbitration between model-free and model-based decision making. Support for this hypothesis derives from emerging functional imaging findings. A deficit in arbitration in OCD may help reconcile evidence for excessive reliance on habit in rewarded learning tasks with an older literature suggesting inappropriate recruitment of circuitry associated with model-based decision making in unreinforced procedural learning. The hypothesized deficit and corresponding circuitry may be a particularly fruitful target for interventions, including cognitive remediation.

Ca2+ Dependence of Synaptic Vesicle Endocytosis

Abstract: Ca(2+)-dependent synaptic vesicle recycling is essential for structural homeostasis of synapses and maintenance of neurotransmission. Although, the executive role of intrasynaptic Ca(2+) transients in synaptic vesicle exocytosis is well established, identifying the exact role of Ca(2+) in endocytosis has been difficult. In some studies, Ca(2+) has been suggested as an essential trigger required to initiate synaptic vesicle retrieval, whereas others manipulating synaptic Ca(2+) concentrations reported a modulatory role for Ca(2+) leading to inhibition or acceleration of endocytosis. Molecular studies of synaptic vesicle endocytosis, on the other hand, have consistently focused on the roles of Ca(2+)-calmodulin dependent phosphatase calcineurin and synaptic vesicle protein synaptotagmin as potential Ca(2+) sensors for endocytosis. Most studies probing the role of Ca(2+) in endocytosis have relied on measurements of synaptic vesicle retrieval after strong stimulation. Strong stimulation paradigms elicit fusion and retrieval of multiple synaptic vesicles and therefore can be affected by several factors besides the kinetics and duration of Ca(2+) signals that include the number of exocytosed vesicles and accumulation of released neurotransmitters thus altering fusion and retrieval processes indirectly via retrograde signaling. Studies monitoring single synaptic vesicle endocytosis may help resolve this conundrum as in these settings the impact of Ca(2+) on synaptic fusion probability can be uncoupled from its putative role on synaptic vesicle retrieval. Future experiments using these single vesicle approaches will help dissect the specific role(s) of Ca(2+) and its sensors in synaptic vesicle endocytosis.

Roles of Calcium Stores and Store-Operated Channels in Plasticity of Dendritic Spines

Abstract: Calcium stores in the endoplasmic reticulum play important roles in a variety of mammalian cellular functions. However, the multitude of calcium-handling machineries in neurons, including voltage- and ligand-gated channels, calcium-binding proteins, pumps, and transporters, as well as the rapid mobility of calcium ions among different cellular compartments hampered the singling out of calcium stores as a pivotal player in synaptic plasticity. Despite these methodological obstacles, novel molecular and imaging tools afforded a rapid progress in deciphering the role of specific calcium stores in neuronal functions. In the present review, we will address several key issues related to the involvement of ryanodine receptors and the calcium entry channel Orai1 in dendritic spine development and plasticity as well as their derailing in neurodegenerative diseases.

Microgliosis in the Injured Brain Infiltrating Cells and Reactive Microglia Both Play a Role

Abstract: Microgliosis is an intense reaction of CNS microglia to pathogenic insults. One of the characteristic features of microgliosis is an increase in the number of activated microglia at the site of lesion. Ontogenically, microglia are considered to be of mesodermal lineage in the adult CNS, but the origin of the accumulated microglia in pathological conditions remains controversial. Some studies indicate that circulating cells from the bloodstream can infiltrate the CNS and contribute to microglial pool, but some studies suggest that local expansion of reactive microglia is the sole source for parenchymal microglia. Recent data suggest that latent progenitors may also exist in the CNS. Available evidence suggests that multiple sources of microglia may exist under various neurological conditions. In this review, we compare the prevalent views and supporting evidence from different experimental models and provide an overview on the origins of microgliosis.

Games in the Brain Neural Substrates of Gambling Addiction

Abstract: As a popular form of recreational risk taking, gambling games offer a paradigm for decision neuroscience research. As an individual behavior, gambling becomes dysfunctional in a subset of the population, with debilitating consequences. Gambling disorder has been recently reconceptualized as a "behavioral addiction" in the DSM-5, based on emerging parallels with substance use disorders. Why do some individuals undergo this transition from recreational to disordered gambling? The biomedical model of problem gambling is a "brain disorder" account that posits an underlying neurobiological abnormality. This article first delineates the neural circuitry that underpins gambling-related decision making, comprising ventral striatum, ventromedial prefrontal cortex, dopaminergic midbrain, and insula, and presents evidence for pathophysiology in this circuitry in gambling disorder. These biological dispositions become translated into clinical disorder through the effects of gambling games. This influence is better articulated in a public health approach that describes the interplay between the player and the (gambling) product. Certain forms of gambling, including electronic gambling machines, appear to be overrepresented in problem gamblers. These games harness psychological features, including variable ratio schedules, near-misses, "losses disguised as wins," and the illusion of control, which modulate the core decision-making circuitry that is perturbed in gambling disorder.

Building a Terminal: Mechanisms of Presynaptic Development in the CNS

Abstract: To create a presynaptic terminal, molecular signaling events must be orchestrated across a number of subcellular compartments. In the soma, presynaptic proteins need to be synthesized, packaged together, and attached to microtubule motors for shipment through the axon. Within the axon, transport of presynaptic packages is regulated to ensure that developing synapses receive an adequate supply of components. At individual axonal sites, extracellular interactions must be translated into intracellular signals that can incorporate mobile transport vesicles into the nascent presynaptic terminal. Even once the initial recruitment process is complete, the components and subsequent functionality of presynaptic terminals need to constantly be remodeled. Perhaps most remarkably, all of these processes need to be coordinated in space and time. In this review, we discuss how these dynamic cellular processes occur in neurons of the central nervous system in order to generate presynaptic terminals in the brain.