Showing papers on "Nervous system published in 2013"
TL;DR: It is demonstrated that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice.
Abstract: Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions.
645 citations
TL;DR: The aquaporins (AQPs) are plasma membrane water-transporting proteins that are expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation, and are potential drug targets for several neurological conditions.
Abstract: The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage.
582 citations
TL;DR: Together with reprogramming technology, human somatic cell-derived NSCs and their progeny can model neurological diseases with improved accuracy and anticipate further important discoveries and novel therapies based on the knowledge and application of these powerful cells.
468 citations
TL;DR: A crucial role for the nervous system is demonstrated in mediating the diverse physiologic and pharmacologic actions of FGF21, which increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response.
Abstract: Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth; however, the site of action of these diverse effects remains unclear FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho, a single-pass transmembrane protein that is enriched in metabolic tissues Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21
431 citations
TL;DR: This review aims to summarize various ways peripheral nerve injuries are classified in light of decades of research on peripheral nerve injury and regeneration.
419 citations
TL;DR: How viruses gain access to and spread in the well-protected CNS is reviewed, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.
403 citations
TL;DR: Current work has demonstrated that oligodendrocytes transfer exosomes to neurons as a result of neurotransmitter signaling suggesting that these vesicles may mediate glial support of neurons.
Abstract: In the nervous system, glia cells maintain homeostasis, synthesize myelin, provide metabolic support, and participate in immune defense. The communication between glia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), such as exosomes and shedding microvesicles, are key players in intercellular signaling. The cells of the nervous system secrete EVs, which potentially carry protein and RNA cargo from one cell to another. After delivery, the cargo has the ability to modify the target cell phenotype. Here, we review the recent advances in understanding the role of EV secretion by astrocytes, microglia, and oligodendrocytes in the central nervous system. Current work has demonstrated that oligodendrocytes transfer exosomes to neurons as a result of neurotransmitter signaling suggesting that these vesicles may mediate glial support of neurons.
311 citations
TL;DR: Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting.
Abstract: The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.
280 citations
TL;DR: Current knowledge about the mechanical properties of nervous tissue and its building blocks is summarized, recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system is reviewed, and an outlook on the implications of neuromechanics for future developments in biomedical engineering is provided.
Abstract: Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis.
254 citations
TL;DR: Electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system in germ-free (GF) mice compared with specific pathogen‐free (SPF) control mice and adult germ‐free mice that have been conventionalized with intestinal bacteria are examined.
Abstract: Background The role of intestinal microbiota in the development and function of host physiology is of high interest, especially with respect to the nervous system. While strong evidence has accrued that intestinal bacteria alter host nervous system function, mechanisms by which this occurs have remained elusive. For this reason, we have carried out experiments examining the electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system (ENS) in germ-free (GF) mice compared with specific pathogen-free (SPF) control mice and adult germ-free mice that have been conventionalized (CONV-GF) with intestinal bacteria.
Methods Segments of jejunum from 8 to 12 week old GF, SPF, and CONV-GF mice were dissected to expose the myenteric plexus. Intracellular recordings in current-clamp mode were made by impaling cells with sharp microelectrodes. Action potential (AP) shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured.
Key Results In GF mice, excitability was decreased in myenteric afterhyperpolarization (AH) neurons as measured by a lower resting membrane potential and by the number of APs generated at 2× threshold. The post AP slow afterhyperpolarization (sAHP) was prolonged for GF compared with SPF and CONV-GF animals. Passive membrane characteristics were also altered in GF mice by a decrease in input resistance.
Conclusions & Inferences Here, we report the novel finding that commensal intestinal microbiota are necessary for normal excitability of gut sensory neurons and thus provide a potential mechanism for the transfer of information between the microbiota and nervous system.
240 citations
TL;DR: A survey on current experimental and clinical state of knowledge about the effect of lavender on the nervous system is given.
Abstract: Lavender is traditionally alleged to have a variety of therapeutic and curative properties, ranging from inducing relaxation to treating parasitic infections, burns, insect bites, and spasm. There is growing evidence suggesting that lavender oil may be an effective medicament in treatment of several neurological disorders. Several animal and human investigations suggest anxiolytic, mood stabilizer, sedative, analgesic, and anticonvulsive and neuroprotective properties for lavender. These studies raised the possibility of revival of lavender therapeutic efficacy in neurological disorders. In this paper, a survey on current experimental and clinical state of knowledge about the effect of lavender on the nervous system is given.
TL;DR: This article focuses on a few examples of nervous system diseases where the contribution of NMDARs is relatively well characterized and discusses the implications for potential treatment of these illnesses.
TL;DR: Different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis will be reviewed, and the role of Wnt pathway components on Alzheimer’s disease will be revised.
Abstract: The Wnt signaling pathway plays a role in the development of the central nervous system (CNS) and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or β-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer’s disease will be revised.
TL;DR: This work generated a wide variety of transgenic zebrafish that expressed reporter genes in specific classes of neurons or neuronal progenitors that examined domain organization in the developing dorsal spinal cord and systematically characterized neurotransmitter properties of the neurons that are produced from each domain.
Abstract: The developing nervous system consists of a variety of cell types. Transgenic animals expressing reporter genes in specific classes of neuronal cells are powerful tools for the study of neuronal network formation. We generated a wide variety of transgenic zebrafish that expressed reporter genes in specific classes of neurons or neuronal progenitors. These include lines in which neurons of specific neurotransmitter phenotypes expressed fluorescent proteins or Gal4, and lines in which specific subsets of the dorsal progenitor domain in the spinal cord expressed fluorescent proteins. Using these, we examined domain organization in the developing dorsal spinal cord, and found that there are six progenitor domains in zebrafish, which is similar to the domain organization in mice. We also systematically characterized neurotransmitter properties of the neurons that are produced from each domain. Given that reporter gene expressions occurs in a wide area of the nervous system in the lines generated, these transgenic fish should serve as powerful tools for the investigation of not only the neurons in the dorsal spinal cord but also neuronal structures and functions in many other regions of the nervous system.
TL;DR: Current knowledge regarding macrophage broad spectrum of activities in the CNS is gathered, and a special focus is devoted to current evidence suggesting that resident microglia and infiltrating monocyte‐derived macrophages are functionally non‐redundant cell types.
Abstract: The central nervous system (CNS) tissues, including the brain, the eye, and the spinal cord, are immune-privileged, secluded from the circulation by a complex of barriers, and equipped with their own myeloid cell population, the resident microglia. Based on the classical perspective of immune-brain interactions and on the contribution of such interactions to the progression of multiple sclerosis, an autoimmune inflammatory disease of the CNS, infiltrating macrophages were traditionally viewed as an enemy of the nervous system. However, over the past two decades, research has revealed the pivotal role of monocyte-derived macrophages in CNS repair, and opened up a new era in understanding and treating CNS pathologies. Here, we gather current knowledge regarding macrophage broad spectrum of activities in the CNS, whose two poles correspond to the classical pro-inflammatory M1 and the 'alternatively-activated' M2 cells previously described in various non-CNS pathologies, and their diverse, multi-functional contribution in various neurological conditions, ranging from acute traumas to neurodegenerative disorders, and autoimmune diseases. The diverse functions are manifested by induction and resolution of inflammation as well as their involvement in neural tissue regeneration and renewal, matrix remodelling, debris clearance, and angiogenesis. A special focus is devoted to current evidence suggesting that resident microglia and infiltrating monocyte-derived macrophages are functionally non-redundant cell types. Taken together, these recent advances reveal a dramatic therapeutic opportunity for controlled harnessing of macrophages for repair of the damaged CNS following acute insults, in neurodegenerative conditions, and in psychiatric disorders.
TL;DR: Evidence for the vulnerability of neurons to energy deprivation, the importance of oligodendrocytes for axon function and survival, and recent data suggesting that transfer of energy metabolites from oligodendedroglia to axons through monocarboxylate transporter 1 (MCT1) may be critical for the survival of axons are discussed.
TL;DR: It is hypothesize that several steps during nervous system development, including neural progenitor cell differentiation, neuronal migration, axon extension and the folding of the brain, rely on or are even driven by mechanical cues and forces.
Abstract: The development of the nervous system has so far, to a large extent, been considered in the context of biochemistry, molecular biology and genetics. However, there is growing evidence that many biological systems also integrate mechanical information when making decisions during differentiation, growth, proliferation, migration and general function. Based on recent findings, I hypothesize that several steps during nervous system development, including neural progenitor cell differentiation, neuronal migration, axon extension and the folding of the brain, rely on or are even driven by mechanical cues and forces.
TL;DR: Previously considered a rare event, nervous system involvement in scleroderma has been increasingly recognized, and seizures and headache are the most reported features in LS en coup de sabre, while peripheral and autonomic nervous systems involvement predominate in SSc.
TL;DR: It is reported that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents and suggests that targeting the W NT signaling pathway may be an effective approach for treating neuropathy pain, including bone cancer pain.
Abstract: Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain-inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.
TL;DR: The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue.
TL;DR: Chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitized (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and Neuro-glial interactions.
Abstract: Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas-related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions.
TL;DR: Data demonstrate that phagocytic glia engulf synaptic and/or axonal elements in the developing nervous system and disruptions in this process result in sustained deficits in synaptic connectivity.
TL;DR: Data highlight the relevance of glial cells in chemotherapy-induced neurotoxicity as part of the investigation of the role that specific brain areas play in neuropathy.
TL;DR: A model in which Gpr126 functions in SCs for proper development and myelination is supported and evidence that these functions are mediated via G-protein-signaling pathways is provided.
Abstract: The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) Gpr126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which Gpr126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether Gpr126 couples to G-proteins. Here, we analyze DhhCre;Gpr126fl/fl conditional mutants, and show that Gpr126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in Gpr126 mouse mutants and that cAMP levels are reduced in conditional Gpr126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which Gpr126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways.
TL;DR: It is found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate, and this findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.
Abstract: Oxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity.
TL;DR: It is observed that neurotransmitter release from olfactory sensory neurons themselves was selectively enhanced for threat-predictive odors after fear conditioning, and affective information about a stimulus can be encoded in its very earliest representation in the nervous system.
Abstract: The central nervous system rapidly learns that particular stimuli predict imminent danger. This learning is thought to involve associations between neutral and harmful stimuli in cortical and limbic brain regions, though associative neuroplasticity in sensory structures is increasingly appreciated. We observed the synaptic output of olfactory sensory neurons (OSNs) in individual mice before and after they learned that a particular odor indicated an impending foot shock. OSNs are the first cells in the olfactory system, physically contacting the odor molecules in the nose and projecting their axons to the brain’s olfactory bulb. OSN output evoked by the shock-predictive odor was selectively facilitated after fear conditioning. These results indicate that affective information about a stimulus can be encoded in its very earliest representation in the nervous system.
TL;DR: Findings indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS, and components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.
Abstract: The concept that target tissues determine the survival of neurons has inspired much of the thinking on neuronal development in vertebrates, not least because it is supported by decades of research on nerve growth factor (NGF) in the peripheral nervous system (PNS). Recent discoveries now help to understand why only some developing neurons selectively depend on NGF. They also indicate that the survival of most neurons in the central nervous system (CNS) is not simply regulated by single growth factors like in the PNS. Additionally, components of the cell death machinery have begun to be recognized as regulators of selective axonal degeneration and synaptic function, thus playing a critical role in wiring up the nervous system.
TL;DR: In this review, examples of the communication between the nervous and the immune systems in the interest of normal CNS development and function are provided.
Abstract: The nervous system and the immune system are two main regulators of homeostasis in the body. Communication between them ensures normal functioning of the organism. Immune cells and molecules are required for sculpting the circuitry and determining the activity of the nervous system. Within the parenchyma of the central nervous system (CNS), microglia constantly monitor synapses and participate in their pruning during development and possibly also throughout life. Classical inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF), are released during neuronal activity and play a crucial role in regulating the strength of synaptic transmission. Systemically, proper functioning of the immune system is critical for maintaining normal nervous system function. Disruption of the immune system functioning leads to impairments in cognition and in neurogenesis. In this review we provide examples of the communication between the nervous and the immune systems in the interest of normal CNS development and function.
TL;DR: The currently known or suggested actions of M MP-2 and MMP-9 in the developing and adult nervous system and their potential to improve repair or regeneration after nervous system injury are highlighted.
TL;DR: Findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.
Abstract: Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest-derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft-derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.