Patients with small fibre neuropathy typically manifest pain in distal extremities and severe autonomic dysfunction. However, occasionally patients present with minimal autonomic symptoms. The basis ...for this phenotypic difference is not understood. Sodium channel Na(v)1.7, encoded by the SCN9A gene, is preferentially expressed in the peripheral nervous system within sensory dorsal root ganglion and sympathetic ganglion neurons and their small diameter peripheral axons. We recently reported missense substitutions in SCN9A that encode functional Na(v)1.7 variants in 28% of patients with biopsy-confirmed small fibre neuropathy. Two patients with biopsy-confirmed small fibre neuropathy manifested minimal autonomic dysfunction unlike the other six patients in this series, and both of these patients carry the Na(v)1.7/R185H variant, presenting the opportunity to compare variants associated with extreme ends of a spectrum from minimal to severe autonomic dysfunction. Herein, we show by voltage-clamp that R185H variant channels enhance resurgent currents within dorsal root ganglion neurons and show by current-clamp that R185H renders dorsal root ganglion neurons hyperexcitable. We also show that in contrast, R185H variant channels do not produce detectable changes when studied by voltage-clamp within sympathetic neurons of the superior cervical ganglion, and have no effect on the excitability of these cells. As a comparator, we studied the Na(v)1.7 variant I739V, identified in three patients with small fibre neuropathy characterized by severe autonomic dysfunction as well as neuropathic pain, and show that this variant impairs channel slow inactivation within both dorsal root ganglion and superior cervical ganglion neurons, and renders dorsal root ganglion neurons hyperexcitable and superior cervical ganglion neurons hypoexcitable. Thus, we show that R185H, from patients with minimal autonomic dysfunction, does not produce detectable changes in the properties of sympathetic ganglion neurons, while I739V, from patients with severe autonomic dysfunction, has a profound effect on excitability of sympathetic ganglion neurons.
Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways ...underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros
) mice show defects in motor functions and die before 6 months of age. Nrros
mice display astrogliosis and lack normal CD11b
CD45
microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros
CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.
Summary Almost every disorder of the CNS is said to have an inflammatory component, but the precise nature of inflammation in the CNS is often imprecisely defined, and the role of CNS-resident cells ...is uncertain compared with that of cells that invade the tissue from the systemic immune compartment. To understand inflammation in the CNS, the term must be better defined, and the response of tissue to disturbances in homoeostasis (eg, neurodegenerative processes) should be distinguished from disorders in which aberrant immune responses lead to CNS dysfunction and tissue destruction (eg, autoimmunity). Whether the inflammatory tissue response to injury is reparative or degenerative seems to be dependent on context and timing, as are the windows of opportunity for therapeutic intervention in inflammatory CNS diseases.
In the past two decades, several advancements have improved the care of HIV-infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has ...resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies--treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism--are needed to reverse or improve HAND-related neurological dysfunction.
The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated ...hyperpermeability, a potential therapeutic target, has not been established.
We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.
We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.
These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.
Background
Although coronavirus disease 2019 (COVID‐19) has been associated primarily with pneumonia, recent data show that the causative agent of COVID‐19, the coronavirus severe acute respiratory ...syndrome coronavirus 2 (SARS‐CoV‐2), can infect a large number of vital organs beyond the lungs, such as the heart, kidneys, and the brain. Thus, there is evidence showing possible retrograde transmission of the virus from the olfactory epithelium to regions of the brain stem.
Methods
This is a literature review article. The research design method is an evidence‐based rapid review. The present discourse aim is first to scrutinize and assess the available literature on COVID‐19 repercussion on the central nervous system (CNS). Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed.
Results
The angiotensin‐converting enzyme 2 (ACE2) receptors being the receptor for the virus, the threat to the central nervous system is expected. Neurons and glial cells express ACE2 receptors in the CNS, and recent studies suggest that activated glial cells contribute to neuroinflammation and the devastating effects of SARS‐CoV‐2 infection on the CNS. The SARS‐CoV‐2‐induced immune‐mediated demyelinating disease, cerebrovascular damage, neurodegeneration, and depression are some of the neurological complications discussed here.
Conclusion
This review correlates present clinical manifestations of COVID‐19 patients with possible neurological consequences in the future, thus preparing healthcare providers for possible future consequences of COVID‐19.
This review correlates present clinical manifestations of coronavirus disease 2019 patients with possible neurological consequences. Recent studies suggest that activated glial cells contribute to neuroinflammation and the devastating effects of severe acute respiratory syndrome coronavirus 2 infection on the central nervous system.
Summary
Background
Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in ...thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS).
Objectives
To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion.
Methods
We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016.
Results and Conclusions
Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. β‐adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of β‐adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis.
What's already known about this topic?
There are two main kinds of sweat glands: eccrine and apocrine.
The physiological functions of sweat glands are to maintain body temperature, release waste products and respond to emotional stress.
Sweat secretion is regulated by both central nervous system and autonomic nervous system, through neurotransmitters such as acetylcholine (ACh) and noradrenaline (NA).
Some sweating disorders may be caused by neural anomaly.
What does this study add?
ACh, which is released by sympathetic nerves, acts as a potent stimulator for sweat secretion. We explain why sympathetic nerves release ACh to stimulate sweat secretion.
β‐adrenoceptors are found in adipocytes as well as apocrine glands. These receptors may mediate lipid secretion from apocrine glands for sweat secretion.
Activation of β‐adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration.
Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion.
Translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands.
Linked Comment: Morris‐Jones. Br J Dermatol 2018; 178:1233–1234.
Plain language summary available online
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of ...functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
DNA methylation and its basic function Moore, Lisa D; Le, Thuc; Fan, Guoping
Neuropsychopharmacology (New York, N.Y.),
01/2013, Volume:
38, Issue:
1
Journal Article
Peer reviewed
Open access
In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates ...gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
Neuroscience is by definition a multidisciplinary field: some scientists study genes and proteins at the molecular level while others study neural circuitry. A single topic such as the auditory ...system can be studied using techniques from genetics, imaging, biochemistry, or electrophysiology. A young scientist must learn how to read the primary literature and then develop their own experiments. This book offers that scientist an overview of mainstream research techniques, provides guidelines on how to choose one technique over another, offers tips on analyzing data, and provides a list of references for additional detailed study. This book can also assist an experienced scientist understand published studies conducted outside their own subfield. *Written by Stanford University graduate students in neuroscience to provide a "hands-on" approach for other neuroscience graduate students *Techniques within one field will be compared so that user can select best technique for their experiment *Chapters include references (key articles, books, protocols) for additional detailed study *Data Analysis boxes in each chapter help with data interpretation andoffer guidelines on how best to represent results *"Walk-through" boxes guide students through the experiment step-by-step
PDF
