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Showing papers on "Nervous system published in 2015"


Journal ArticleDOI
TL;DR: There is much evidence that autonomic control of the airways may be abnormal in airway disease, particularly in asthma, but the precise role of neural mechanisms in the pathogenesis of air-flow obstruction and bronchial hyperresponsiveness remains to be defined.
Abstract: Several aspects of airway function are under autonomic control: airway smooth muscle tone, submucosal gland secretion, epithelial cell function, bronchial vascular tone and permeability, and probably secretion from mast cells and other inflammatory cells. Neural control of human airways is more complex than previously recognized. In addition to afferent nerves and cholinergic adrenergic mechanisms (including circulating catecholamines), there are nonadrenergic, noncholinergic nerves that may be both excitatory and inhibitory. The neurotransmitters of this third nervous system are uncertain, but there is some evidence that neuropeptides may be involved. Several neuropeptides have recently been identified in human airways and, although they have potent effects, their pathophysiologic role is uncertain. There is much evidence that autonomic control of the airways may be abnormal in airway disease, particularly in asthma, but the precise role of neural mechanisms in the pathogenesis of air-flow obstruction and bronchial hyperresponsiveness remains to be defined.

611 citations


Journal ArticleDOI
TL;DR: The new research on activity-dependent myelination is summarized, the possible implications of these studies are explored, and the potential for new research is outlined.
Abstract: The precise timing of impulse transmission along axons is crucial for synaptic plasticity and brain oscillations, and is partly determined by myelin thickness. In this Opinion article, R. Douglas Fields discusses how electrical activity influences myelin thickness and thus conduction velocity and circuit properties.

553 citations


Journal ArticleDOI
TL;DR: Recent findings demonstrating how the dynamic interactions between neurons and microglia shape the circuitry of the nervous system in the healthy brain and how altered neuron-microglia signaling could contribute to disease are reviewed.

491 citations


Book
20 Apr 2015
TL;DR: A detailed overview of the human brain can be found in this article, where the authors describe the development of the Nervous System and the organization of the central nervous system, as well as the chemical senses of taste and smell.
Abstract: 1. Introduction to the Nervous System 2. Development of the Nervous System 3. Gross Anatomy and General Organization of the Central Nervous System 4. Meningeal Coverings of the Brain and Spinal Cord 5. Ventricles and Cerebrospinal Fluid 6. Blood Supply of the Brain 7. Electrical Signaling by Neurons 8. Synaptic Transmission Between Neurons 9. Sensory Receptors and the Peripheral Nervous System 10. Spinal Cord 11. Organization of the Brain Stem 12. Cranial Nerves and Their Nuclei 13. The Chemical Senses of Taste and Smell 14. Hearing and Balance: The Eighth Cranial Nerve 15. Atlas of the Human Brainstem 16. The Thalmus and Internal Capsule: Getting to and from the Cerebral Cortex 17. The Visual System 18. Overview of Motor System 19. Basal Nuclei 20. Cerebellum 21. Eye Movements 22. Cerebral Cortex 23. Drives and Emotions: The Hypothalmus and Limbic System 24. Formation, Modification, and Repair of Neuronal Connections 25. Atlas of the Human Forebrain

415 citations


Journal ArticleDOI
TL;DR: It is determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon, and this neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.
Abstract: Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit’s functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.

317 citations


Journal ArticleDOI
25 Dec 2015-eLife
TL;DR: It is found that acetylcholine (ACh) is the most broadly used neurotransmitter and its usage relative to other neurotransmitters within the context of the entire connectome and within specific network motifs embedded in the connectome.
Abstract: Neurotransmitter maps are important complements to anatomical maps and represent an invaluable resource to understand nervous system function and development. We report here a comprehensive map of neurons in the C. elegans nervous system that contain the neurotransmitter GABA, revealing twice as many GABA-positive neuron classes as previously reported. We define previously unknown glia-like cells that take up GABA, as well as 'GABA uptake neurons' which do not synthesize GABA but take it up from the extracellular environment, and we map the expression of previously uncharacterized ionotropic GABA receptors. We use the map of GABA-positive neurons for a comprehensive analysis of transcriptional regulators that define the GABA phenotype. We synthesize our findings of specification of GABAergic neurons with previous reports on the specification of glutamatergic and cholinergic neurons into a nervous system-wide regulatory map which defines neurotransmitter specification mechanisms for more than half of all neuron classes in C. elegans.

301 citations


Journal ArticleDOI
TL;DR: A new neuronal medium is designed and tested in which the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates are adjusted in which this medium adequately supports neuronal activity and survival of human neurons in culture.
Abstract: Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

292 citations


Journal ArticleDOI
TL;DR: Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias.
Abstract: Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.

266 citations


Journal ArticleDOI
TL;DR: A historical perspective of work to identify microglia function in the healthy CNS is given and exciting new work in the field that has identified roles for these cells in CNS development, maintenance, and plasticity is highlighted.
Abstract: The nervous system comprises a remarkably diverse and complex network of different cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in the spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS and highlight exciting new work in the field that has identified roles for these cells in CNS development, maintenance, and plasticity.

264 citations


Journal ArticleDOI
TL;DR: The origins of glia are reviewed, their diverse roles during neural development and their contribution to plasticity and disease in the adult mammalian nervous system are discussed.
Abstract: Glia account for more than half of the cells in the mammalian nervous system, and the past few decades have witnessed a flood of studies that detail novel functions for glia in nervous system development, plasticity and disease. Here, and in the accompanying poster, we review the origins of glia and discuss their diverse roles during development, in the adult nervous system and in the context of disease.

259 citations


Journal ArticleDOI
18 Feb 2015-Neuron
TL;DR: This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of L PA to both physiological and diseased states.

Journal ArticleDOI
18 Feb 2015-Neuron
TL;DR: GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation, and this work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development.

Journal ArticleDOI
TL;DR: It is shown using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodENDroglial cells are not required and vesicular release at nonsynaptic axo-glial junctions induces myelination.
Abstract: The myelin sheath on vertebrate axons is critical for neural impulse transmission, but whether electrically active axons are preferentially myelinated by glial cells, and if so, whether axo-glial synapses are involved, are long-standing questions of significance to nervous system development, plasticity and disease. Here we show using an in vitro system that oligodendrocytes preferentially myelinate electrically active axons, but synapses from axons onto myelin-forming oligodendroglial cells are not required. Instead, vesicular release at nonsynaptic axo-glial junctions induces myelination. Axons releasing neurotransmitter from vesicles that accumulate in axon varicosities induces a local rise in cytoplasmic calcium in glial cell processes at these nonsynaptic functional junctions, and this signalling stimulates local translation of myelin basic protein to initiate myelination.

Journal ArticleDOI
13 Jan 2015-Evodevo
TL;DR: It is argued that characters like neuropeptide signaling, ciliary photoreceptors, gap junctions and presynaptic molecules are consistent with a shared ancestry of nervous systems, however, that phylogenetic-tree construction artifacts may have placed ctenophores too deep in the metazoan tree.
Abstract: Ctenophores have traditionally been treated as eumetazoans, but some recent whole genome studies have revived the idea that they are, rather, the sister group to all other metazoans. This deep branching position implies either that nervous systems have evolved twice, in Ctenophora and in Eumetazoa, or that an ancestral metazoan nervous system has been lost in sponges and placozoans. We caution, however, that phylogenetic-tree construction artifacts may have placed ctenophores too deep in the metazoan tree. We discuss nervous system origins under these alternative phylogenies and in light of comparative data of ctenophore and eumetazoan nervous systems. We argue that characters like neuropeptide signaling, ciliary photoreceptors, gap junctions and presynaptic molecules are consistent with a shared ancestry of nervous systems. However, if ctenophores are the sister group to all other metazoans, this ancestral nervous system was likely very simple. Further studies are needed to resolve the deep phylogeny of metazoans and to have a better understanding of the early steps of nervous system evolution.

Journal ArticleDOI
TL;DR: It is shown that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate and differentiates into specific neuronal subtypes in the postnatal period and contributes to the ENS.
Abstract: Elucidation of the cellular identity of neuronal precursors provides mechanistic insights into the development and pathophysiology of the nervous system. In the enteric nervous system (ENS), neurogenesis persists from midgestation to the postnatal period. Cellular mechanism underlying the long-term neurogenesis in the ENS has remained unclear. Using genetic fate mapping in mice, we show here that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate in the postnatal period and contributes to the ENS. We found SCP-derived neurogenesis in the submucosal region of the small intestine in the absence of vagal neural crest-derived ENS precursors. Under physiological conditions, SCPs comprised up to 20% of enteric neurons in the large intestine and gave rise mainly to restricted neuronal subtypes, calretinin-expressing neurons. Genetic ablation of Ret , the signaling receptor for glial cell line-derived neurotrophic factor, in SCPs caused colonic oligoganglionosis, indicating that SCP-derived neurogenesis is essential to ENS integrity. Identification of Schwann cells as a physiological neurogenic source provides novel insight into the development and disorders of neural crest-derived tissues. SIGNIFICANCE STATEMENT Elucidating the cellular identity of neuronal precursors provides novel insights into development and function of the nervous system. The enteric nervous system (ENS) is innervated richly by extrinsic nerve fibers, but little is known about the significance of extrinsic innervation to the structural integrity of the ENS. This report reveals that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate and differentiates into specific neuronal subtypes. SCP-specific ablation of the Ret gene leads to colonic oligoganglionosis, demonstrating a crucial role of SCP-derived neurogenesis in ENS development. Cross-lineage differentiation capacity in SCPs suggests their potential involvement in the development and pathology of a wide variety of neural crest-derived cell types.

Journal ArticleDOI
TL;DR: The neuroprotective effects of progesterone on the nervous system via PR, and of allopregnanolone via its modulation of GABAA receptors are discussed, as well as their effects in different experimental models including stroke and spinal cord injury.

Journal ArticleDOI
TL;DR: This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV), and the first of these antagonists, aprepitant and fosaprepitant, are prescribed for high and moderate emesis.
Abstract: The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

Journal ArticleDOI
TL;DR: In humans, experiments performed in healthy volunteers using drugs already used in the clinic and acting as poorly-selective inhibitors of ASICs, together with recent in vitro data obtained from stem cell-derived sensory neurons both support a role for these channels in nociception, and suggest a real translational potential in the development of inhibitory strategies of ASIC's for the treatment of pain.

Journal ArticleDOI
TL;DR: Novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression are discussed, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth.
Abstract: Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

Book ChapterDOI
TL;DR: A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described and its major component is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine mictsurition center.
Abstract: Functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. Neural control of micturition is organized as a hierarchic system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily during the early postnatal period, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults cause re-emergence of involuntary micturition, leading to urinary incontinence. The mechanisms underlying these pathologic changes are discussed.

Journal ArticleDOI
01 Nov 2015-Glia
TL;DR: Enteric glia are transcriptionally unique and distinct from other cell types in the nervous system, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes.
Abstract: In the enteric nervous system (ENS), glia outnumber neurons by 4-fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100β are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS. GLIA 2015;63:2040-2057.

Journal ArticleDOI
TL;DR: It is made the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation.
Abstract: Cells of the immune system and the central nervous system are capable of interacting with each other. The former cell populations respond to infection, tissue injury and trauma by releasing substances capable of provoking an inflammatory reaction. Inflammation is now recognized as a key feature in nervous system pathologies such as chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders such as anxiety/depression and schizophrenia. Neuroinflammation may also raise the brain's sensitivity to stress, thereby effecting stress-related neuropsychiatric disorders like anxiety or depression. The cytokine network plays a large part in how immune system cells influence the central nervous system. Further, inflammation resulting from activation of innate immune system cells in the periphery can impact on central nervous system behaviors, such as depression and cognitive performance. In this review, we will present the reader with the current state of knowledge which implicates both microglia and mast cells, two of the principle innate immune cell populations, in neuroinflammation. Further, we shall make the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation. Finally, we will use this information to provide a starting point to propose therapeutic approaches based upon naturally-occurring lipid signaling molecules.

Journal ArticleDOI
TL;DR: Key mechanisms that trigger the inflammatory reaction after nervous system trauma are discussed, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules.
Abstract: Traumatic injury to the central nervous system (CNS) or the peripheral nervous system (PNS) triggers a cascade of events which culminate in a robust inflammatory reaction. The role played by inflammation in the course of degeneration and regeneration is not completely elucidated. While, in peripheral nerves, the inflammatory response is assumed to be essential for normal progression of Wallerian degeneration and regeneration, CNS trauma inflammation is often associated with poor recovery. In this review, we discuss key mechanisms that trigger the inflammatory reaction after nervous system trauma, emphasizing how inflammations in both CNS and PNS differ from each other, in terms of magnitude, cell types involved, and effector molecules. Knowledge of the precise mechanisms that elicit and maintain inflammation after CNS and PNS tissue trauma and their effect on axon degeneration and regeneration is crucial for the identification of possible pharmacological drugs that can positively affect the tissue regenerative capacity.

Journal ArticleDOI
TL;DR: It is convinced that in the future the stem cell therapy with the support of functionalized electrospun nerve scaffolds could be a promising therapy to cure nerve diseases.
Abstract: Nerve diseases including acute injury such as peripheral nerve injury (PNI), spinal cord injury (SCI) and traumatic brain injury (TBI), and chronic disease like neurodegeneration disease can cause various function disorders of nervous system, such as those relating to memory and voluntary movement. These nerve diseases produce great burden for individual families and the society, for which a lot of efforts have been made. Axonal pathways represent a unidirectional and aligned architecture allowing systematic axonal development within the tissue. Following a traumatic injury, the intricate architecture suffers disruption leading to inhibition of growth and loss of guidance. Due to limited capacity of the body to regenerate axonal pathways, it is desirable to have biomimetic approach that has the capacity to graft a bridge across the lesion while providing optimal mechanical and biochemical cues for tissue regeneration. And for central nervous system injury, one more extra precondition is compulsory: creating a less inhibitory surrounding for axonal growth. Electrospinning is a cost-effective and straightforward technique to fabricate extracellular matrix (ECM)-like nanofibrous structures, with various fibrous forms such as random fibers, aligned fibers, 3D fibrous scaffold and core-shell fibers from a variety of polymers. The diversity and versatility of electrospinning technique, together with functionalizing cues such as neurotrophins, ECM-based proteins and conductive polymers, have gained considerable success for the nerve tissue applications. We are convinced that in the future the stem cell therapy with the support of functionalized electrospun nerve scaffolds could be a promising therapy to cure nerve diseases.

Journal ArticleDOI
TL;DR: The contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues is examined and opportunities for therapeutic manipulation of neuro-immune interactions are discussed.

Journal ArticleDOI
TL;DR: Critical in vivo neurodevelopmental functions of nSR100 are revealed and a conserved program of neuronal microexon splicing is linked, sufficient to rescue a neuritogenesis defect in nSR 100 mutant primary neurons.
Abstract: Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing

Book ChapterDOI
TL;DR: The general features of the EC system are described as related to pain and nociception and the wealth of preclinical and clinical data involving targeting theEC system is discussed, with focus on modulation of 2-AG signalling via specific enzyme inhibitors and the role of spinal CB2 in chronic pain states.
Abstract: Preparations of the Cannabis sativa plant have been used to analgesic effect for millenia, but only in recent decades has the endogenous system responsible for these effects been described The endocannabinoid (EC) system is now known to be one of the key endogenous systems regulating pain sensation, with modulatory actions at all stages of pain processing pathways The EC system is composed of two main cannabinoid receptors (CB1 and CB2) and two main classes of endogenous ligands or endocannabinoids (ECs) The receptors have distinct expression profiles, with CB1 receptors found at presynaptic sites throughout the peripheral and central nervous systems (PNS and CNS, respectively), whilst CB2 receptor is found principally (but not exclusively) on immune cells The endocannabinoid ligands are lipid neurotransmitters belonging to either the N-acyl ethanolamine (NAEs) class, eg anandamide (AEA), or the monoacylglycerol class, eg 2-arachidonoyl glycerol (2-AG) Both classes are short-acting transmitter substances, being synthesised on demand and with signalling rapidly terminated by specific enzymes ECs acting at CB1 negatively regulate neurotransmission throughout the nervous system, whilst those acting at CB2 regulate the activity of CNS immune cells Signalling through both of these receptor subtypes has a role in normal nociceptive processing and also in the development resolution of acute pain states In this chapter, we describe the general features of the EC system as related to pain and nociception and discuss the wealth of preclinical and clinical data involving targeting the EC system with focus on two areas of particular promise: modulation of 2-AG signalling via specific enzyme inhibitors and the role of spinal CB2 in chronic pain states

Journal ArticleDOI
TL;DR: The findings of the expression patterns of CB2R mRNAs may help determine the cell types involved in, and hence the mechanisms of, theCB2R-mediated neuromodulation.

Journal ArticleDOI
TL;DR: The role of CD44 in the physiology and pathology of the nervous system is not entirely understood, however, there exists evidence suggesting it might be involved in the axon guidance, cytoplasmic Ca2+ clearance, dendritic arborization, synaptic transmission, epileptogenesis, oligodendrocytes and astrocyte differentiation, post-traumatic brain repair and brain tumour development.
Abstract: CD44 is the major surface hyaluronan receptor implicated in intercellular and cell-matrix adhesion, cell migration and signalling. It is a transmembrane, highly glycosylated protein with several isoforms resulting from alternative gene splicing. The CD44 molecule consists of several domains serving different functions: the N-terminal extracellular domain, the stem region, the transmembrane domain and the C-terminal tail. In the nervous system, CD44 expression occurs in both glial and neuronal cells. The role of CD44 in the physiology and pathology of the nervous system is not entirely understood, however, there exists evidence suggesting it might be involved in the axon guidance, cytoplasmic Ca2+ clearance, dendritic arborization, synaptic transmission, epileptogenesis, oligodendrocyte and astrocyte differentiation, post-traumatic brain repair and brain tumour development.

Journal ArticleDOI
08 Jun 2015-eLife
TL;DR: It is demonstrated that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model are linked.
Abstract: Dystonia is disorder of the nervous system that causes people to suffer from abnormal and involuntary twisting movements. These movements are triggered, in part, by irregularities in a part of the brain called the striatum. The most common view among researchers is that dystonia is caused by abnormal activity in an otherwise structurally normal nervous system. But, recent findings indicate that the degeneration of small populations of nerve cells in the brain may be important. The striatum is made up of several different types of nerve cells, but it is poorly understood which of these are affected in dystonia. One type of dystonia, which most often occurs in children, is caused by a defect in a protein called torsinA. Pappas et al. have now discovered that deleting the gene for torsinA from particular populations of nerve cells in the brains of mice (including a population in the striatum) causes abnormal twisting movements. Like people with dystonia, these mice developed the abnormal movements as juveniles, and the movements were suppressed with ‘anti-cholinergic’ medications. Pappas et al. then analyzed brain tissue from these mice and revealed that the twisting movements began at the same time that a single type of cell in the striatum—called ‘cholinergic interneurons’—degenerated. Postmortem studies of brain tissue from dystonia patients also revealed abnormalities of these neurons. Together these findings challenge the notion that dystonia occurs in a structurally normal nervous system and reveal that cholinergic interneurons in the striatum specifically require torsinA to survive. Following on from this work, the next challenges are to identify what causes the selective loss of cholinergic interneurons, and to investigate how this cell loss affects the activity within the striatum.