Components Of Central Nervous System Research Articles

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

NMDA Receptors in Neurodevelopmental Disorders: Pathophysiology and Disease Models.

N-methyl-D-aspartate receptors (NMDARs) are critical components of the mammalian central nervous system, involved in synaptic transmission, plasticity, and neurodevelopment. This review focuses on the structural and functional characteristics of NMDARs, with a particular emphasis on the GRIN2 subunits (GluN2A-D). The diversity of GRIN2 subunits, driven by alternative splicing and genetic variants, significantly impacts receptor function, synaptic localization, and disease manifestation. The temporal and spatial expression of these subunits is essential for typical neural development, with each subunit supporting distinct phases of synaptic formation and plasticity. Disruptions in their developmental regulation are linked to neurodevelopmental disorders, underscoring the importance of understanding these dynamics in NDD pathophysiology. We explore the physiological properties and developmental regulation of these subunits, highlighting their roles in the pathophysiology of various NDDs, including ASD, epilepsy, and schizophrenia. By reviewing current knowledge and experimental models, including mouse models and human-induced pluripotent stem cells (hiPSCs), this article aims to elucidate different approaches through which the intricacies of NMDAR dysfunction in NDDs are currently being explored. The comprehensive understanding of NMDAR subunit composition and their mutations provides a foundation for developing targeted therapeutic strategies to address these complex disorders.

Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Proof of mechanism investigation of Transcutaneous auricular vagus nerve stimulation through simultaneous measurement of autonomic functions: a randomized controlled trial protocol

BackgroundThe autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications.MethodsThis protocol employs a single-blind, randomized cross-over design involving 10 healthy male participants. Simultaneous assessment of both the afferent and efferent aspects of the vagus nerve will be performed by integrating physiological measures, magnetic resonance imaging, and a questionnaire survey. Electrocardiogram will be measured to assess changes in heart rate, as a primary outcome, and heart rate variability. Active taVNS and sham stimulation will be compared, which ensures precision and blinding. Electrical stimulation will be applied to the left concha cymba and the left lobule for the active and sham conditions, respectively. The specific parameters of taVNS involve a pulse width of 250 µs, a frequency of 25 Hz, and a current adjusted to the perception threshold (0.1 mA ≤ 5 mA), delivered in cycles of 32 s on and 28 s off.ConclusionsThis research investigates proof of mechanism for taVNS to elucidate its modulatory effects on the central and peripheral components of the autonomic nervous system. Beyond theoretical insights, the findings will provide a foundation for designing targeted neuromodulation strategies, potentially benefiting diverse patient populations experiencing autonomic dysregulation. By elucidating the neural mechanisms, this study contributes to the evolution of personalized and effective clinical interventions in the field of neuromodulation.Trial RegistrationJRCT, jRCTs032220332, Registered 13 September 2022; https://jrct.niph.go.jp/latest-detail/jRCTs032220332.

Exploring the Mechanistic Interplay between Gut Microbiota and Precocious Puberty: A Narrative Review.

The gut microbiota has been implicated in the context of sexual maturation during puberty, with discernible differences in its composition before and after this critical developmental stage. Notably, there has been a global rise in the prevalence of precocious puberty in recent years, particularly among girls, where approximately 90% of central precocious puberty cases lack a clearly identifiable cause. While a link between precocious puberty and the gut microbiota has been observed, the precise causality and underlying mechanisms remain elusive. This narrative review aims to systematically elucidate the potential mechanisms that underlie the intricate relationship between the gut microbiota and precocious puberty. Potential avenues of exploration include investigating the impact of the gut microbiota on endocrine function, particularly in the regulation of hormones, such as gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Additionally, this review will delve into the intricate interplay between the gut microbiome, metabolism, and obesity, considering the known association between obesity and precocious puberty. This review will also explore how the microbiome's involvement in nutrient metabolism could impact precocious puberty. Finally, attention is given to the microbiota's ability to produce neurotransmitters and neuroactive compounds, potentially influencing the central nervous system components involved in regulating puberty. By exploring these mechanisms, this narrative review seeks to identify unexplored targets and emerging directions in understanding the role of the gut microbiome in relation to precocious puberty. The ultimate goal is to provide valuable insights for the development of non-invasive diagnostic methods and innovative therapeutic strategies for precocious puberty in the future, such as specific probiotic therapy.

Cough Sensitivity to Several External Triggers is Associated with Multiple Non-respiratory Symptoms

PurposeEnhanced responsiveness to external triggers is thought to reflect hypersensitivity of the cough reflex. It may involve an enhanced sensitivity of the afferent nerves in the airways and/or an abnormal processing of the afferent information by the central nervous system (CNS). The CNS processing of cough has been shown to involve the same regions as those in symptom amplification, a phenomenon that often manifests as multiple symptoms. The main purpose of the present study was to define whether the presence of several cough triggers is associated with multiple symptoms.Methods2131 subjects with current cough responding to two email surveys filled in a comprehensive questionnaire about social background, lifestyle, general health, doctors’ diagnoses and visits, symptoms, and medication. Multiple symptoms was defined as three or more non-respiratory, non-mental symptoms.ResultsA carefully controlled multiple regression analysis revealed that the number of cough triggers was the only cough characteristic associating with multiple non-respiratory, non-mental symptoms [aOR 1.15 (1.12–1.19) per one trigger, p < 0.001]. Among the 268 subjects with current cough both in the first survey and in the follow-up survey 12 months later, the repeatability of the trigger sum was good with an intraclass correlation coefficient of 0.80 (0.75–0.84).ConclusionThe association between the number of the cough triggers and multiple symptoms suggests that the CNS component of cough hypersensitivity may be a manifestation of non-specific alteration in the CNS interpretation of various body sensations. The number of cough triggers is a repeatable measure of cough sensitivity.

It is time to do better for people with rare neurological conditions

Sue Thomas outlines the UK rare conditions framework and the subsequent action plan that was published in February 2023. Estimates indicate nearly half of all rare diseases are neurological, and as many as 90% of all paediatric rare diseases have a major neurological (central nervous system) component to them, which makes the rare disease policy very relevant to those working in neuroscience settings.

Prognosis of Biomarker of Alzheimer's Disease in the Function of the Retina and Secondary Molecular Structure Variation of the Retina and Brain.

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases in the globe. As a result, there is an acute need to discover indications that allow for early disease detection. There is growing scientific data showing the similarities between the eye and other central nervous system components, suggesting that information obtained in ophthalmic research might be valuable in the study and diagnosis of AD. Fifty male albino Wistar rats were separated into five groups: the first group served as control, and the other four groups of animals were administrated aluminium chloride (AlCl3) in a dose of 100 mg/kg body weight (b.w.) for 2, 4, 6, and 8 weeks, respectively. Insights into the function of the retina by electroretinogram (ERG) and the changes thought to have occurred in the molecular structure of the retina and brain using Fourier transform infrared spectroscopy (FTIR) as a result of AD progression induced by AlCl3 in rats were done. Moreover, the measurement of acetylcholinesterase (AchE) was done. After 6 and 8 weeks of AlCl3 injection, there was a substantial reduction (p ≤ 0.05) in a- and b-wave amplitudes and a significant rise (p ≤ 0.05) in implicit time compared to controls. A significant elevation (p ≤ 0.05) of AchE content was observed after 4, 6, and 8 weeks. FTIR revealed a significant increase (p ≤ 0.05) of β-turn and β-sheet content associated with significant decrease (p ≤ 0.05) of α-helix content for all groups administrated with AlCl3. Our findings suggest that retinal biomarkers such as ERG of the retina may be used as a screening tool for detection of AD. Secondary structural changes in the proteins of the retina and the brain were similar in AD rats' model and precede retinal dysfunction.

Transplantation of Umbilical Cord-Derived Mesenchymal Stem Cells Attenuates Surgical Wound-Induced Blood-Brain Barrier Dysfunction in Mice.

Blood-brain barrier (BBB) is the most important component of central nervous system (CNS) to keep toxins and pathogens from CNS. Although our studies demonstrated that using interleukin-6 antibodies (IL-6-AB) reversed the increased permeability of BBB, IL-6-AB is limited in their application that only could be used a few hours before surgery and seemed delayed the surgical wounds healing process, which urges us to find another more effective method. In this study, we employed the C57BL/6J female mice to investigate the potential effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation on BBB dysfunction induced by surgical wound. Compared to IL-6-AB, the transplantation of UC-MSCs more effectively decreased the BBB permeability after surgical wound evaluated by dextran tracer (immunofluorescence imaging and luorescence quantification). In addition, UC-MSCs can largely decrease the ratio of proinflammatory cytokine IL-6 to the anti-inflammatory cytokine IL-10 in both serum and brain tissue after surgical wound. Moreover, UC-MSCs successfully increased the levels of tight junction proteins (TJs) in BBB such as ZO-1, Occludin, and Claudin-5 and extremely decreased the level of matrix metalloproteinase-9 (MMP-9). Interestingly, UC-MSCs treatment also had positive effects on wound healing while protecting the BBB dysfunction induced by surgical wound compared to IL-6-AB treatment. These findings suggest that UC-MSCs transplantation is a highly efficient and promising approach on protecting the integrity of BBB which caused by peripheral traumatic injuries.

Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury

BackgroundLimited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors.MethodsWe used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery.ResultsAstrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes.ConclusionsA2 astrocyte transplantation could be a promising potential therapy for SCI.Graphical -k_-1M1wXF49hQ9JfigvAZVideo abstract

Betaine-The dark knight of the brain.

The role of betaine in the liver and kidney has been well documented, even from the cellular and molecular point of view. Despite literature reporting positive effects of betaine supplementation in Alzheimer's, Parkinson's and schizophrenia, the role and function of betaine in the brain are little studied and reviewed. Beneficial effects of betaine in neurodegeneration, excitatory and inhibitory imbalance and against oxidative stress in the central nervous system (CNS) have been collected and analysed to understand the main role of betaine in the brain. There are many 'dark' aspects needed to complete the picture. The understanding of how this osmolyte is transported across neuron and glial cells is also controversial, as the expression levels and functioning of the known protein capable to transport betaine expressed in the brain, betaine-GABA transporter 1 (BGT-1), is itself not well clarified. The reported actions of betaine beyond BGT-1 related to neuronal degeneration and memory impairment are the focus of this work. With this review, we underline the scarcity of detailed molecular and cellular information about betaine action. Consequently, the requirement of detailed focus on and study of the interaction of this molecule with CNS components to sustain the therapeutic use of betaine.

Stellate Ganglia and Cardiac Sympathetic Overactivation in Heart Failure.

Heart failure (HF) is a major public health problem worldwide, especially coronary heart disease (myocardial infarction)-induced HF with reduced ejection fraction (HFrEF), which accounts for over 50% of all HF cases. An estimated 6 million American adults have HF. As a major feature of HF, cardiac sympathetic overactivation triggers arrhythmias and sudden cardiac death, which accounts for nearly 50-60% of mortality in HF patients. Regulation of cardiac sympathetic activation is highly integrated by the regulatory circuitry at multiple levels, including afferent, central, and efferent components of the sympathetic nervous system. Much evidence, from other investigators and us, has confirmed the afferent and central neural mechanisms causing sympathoexcitation in HF. The stellate ganglion is a peripheral sympathetic ganglion formed by the fusion of the 7th cervical and 1st thoracic sympathetic ganglion. As the efferent component of the sympathetic nervous system, cardiac postganglionic sympathetic neurons located in stellate ganglia provide local neural coordination independent of higher brain centers. Structural and functional impairments of cardiac postganglionic sympathetic neurons can be involved in cardiac sympathetic overactivation in HF because normally, many effects of the cardiac sympathetic nervous system on cardiac function are mediated via neurotransmitters (e.g., norepinephrine) released from cardiac postganglionic sympathetic neurons innervating the heart. This review provides an overview of cardiac sympathetic remodeling in stellate ganglia and potential mechanisms and the role of cardiac sympathetic remodeling in cardiac sympathetic overactivation and arrhythmias in HF. Targeting cardiac sympathetic remodeling in stellate ganglia could be a therapeutic strategy against malignant cardiac arrhythmias in HF.

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ-opioid receptor.

Tramadol is a synthetic opioid with centrally acting analgesic activity that alleviates moderate to severe pain and treats withdrawal symptoms of the other opioids. Like other opioid drugs, tramadol abuse has adverse effects on central nervous system components. Chronic administration of tramadol induces maladaptive plasticity in brain structures responsible for cognitive function, such as the hippocampus. However, the mechanisms by which tramadol induces these alternations are not entirely understood. Here, we examine the effect of tramadol on apoptosis and synaptogenesis of hippocampal neuronal in vitro. First, the primary culture of hippocampal neurons from neonatal rats was established, and the purity of the neuronal cells was verified by immunofluorescent staining. To evaluate the effect of tramadol on neuronal cell viability MTT assay was carried out. The western blot analysis technique was performed for the assessment of apoptosis and synaptogenesis markers. Results show that chronic exposure to tramadol reduces cell viability of neuronal cells and naloxone reverses this effect. Also, the level of caspase-3 significantly increased in tramadol-exposed hippocampal neurons. Moreover, tramadol downregulates protein levels of synaptophysin and stathmin as synaptogenesis markers. Interestingly, the effects of tramadol were abrogated by naloxone treatment. These findings suggest that tramadol can induce neurotoxicity in hippocampal neuronal cells, and this effect was partly mediated through opioid receptors.

Chromatin Structure and Dynamics: Focus on Neuronal Differentiation and Pathological Implication.

Chromatin structure is an essential regulator of gene expression. Its state of compaction contributes to the regulation of genetic programs, in particular during differentiation. Epigenetic processes, which include post-translational modifications of histones, DNA methylation and implication of non-coding RNA, are powerful regulators of gene expression. Neurogenesis and neuronal differentiation are spatio-temporally regulated events that allow the formation of the central nervous system components. Here, we review the chromatin structure and post-translational histone modifications associated with neuronal differentiation. Studying the impact of histone modifications on neuronal differentiation improves our understanding of the pathophysiological mechanisms of chromatinopathies and opens up new therapeutic avenues. In addition, we will discuss techniques for the analysis of histone modifications on a genome-wide scale and the pathologies associated with the dysregulation of the epigenetic machinery.

Regulation of Voluntary Physical Activity Behavior: A Review of Evidence Involving Dopaminergic Pathways in the Brain.

Physical activity leads to well-established health benefits. Current efforts to enhance physical activity have targeted mainly socioeconomic factors. However, despite these efforts, only a small number of adults engage in regular physical activity to the point of meeting current recommendations. Evidence collected in rodent models and humans establish a strong central nervous system component that regulates physical activity behavior. In particular, dopaminergic pathways in the central nervous system are among the best-characterized biological mechanisms to date with respect to regulating reward, motivation, and habit formation, which are critical for establishing regular physical activity. Herein, we discuss evidence for a role of brain dopamine in the regulation of voluntary physical activity behavior based on selective breeding and pharmacological studies in rodents, as well as genetic studies in both rodents and humans. While these studies establish a role of dopamine and associated mechanisms in the brain in the regulation of voluntary physical activity behavior, there is clearly need for more research on the underlying biology involved in motivation for physical activity and the formation of a physical activity habit. Such knowledge at the basic science level may ultimately be translated into better strategies to enhance physical activity levels within the society.

Clearance Systems in the Brain, From Structure to Function.

As the most metabolically active organ in the body, there is a recognized need for pathways that remove waste proteins and neurotoxins from the brain. Previous research has indicated potential associations between the clearance system in the brain and the pathological conditions of the central nervous system (CNS), due to its importance, which has attracted considerable attention recently. In the last decade, studies of the clearance system have been restricted to the glymphatic system. However, removal of toxic and catabolic waste by-products cannot be completed independently by the glymphatic system, while no known research or article has focused on a comprehensive overview of the structure and function of the clearance system. This thesis addresses a neglected aspect of linkage between the structural composition and main components as well as the role of neural cells throughout the clearance system, which found evidence that the components of CNS including the glymphatic system and the meningeal lymphatic system interact with a neural cell, such as astrocytes and microglia, to carry out vital clearance functions. As a result of this evidence that can contribute to a better understanding of the clearance system, suggestions were identified for further clinical intervention development of severe conditions caused by the accumulation of metabolic waste products and neurotoxins in the brain, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

SARS-CoV-2 vaccine-related neurological complications.

ObjectiveTo describe three cases with neurological symptoms after SARS-CoV-2 vaccination.MethodsA case series followed by a review of the literature, describing hypotheses on how neurological symptoms might develop after vaccination.ResultsThe different temporal relationship between the onset or worsening of different neurological symptoms suggests different pathophysiological mechanisms. Progression of post-infectious myoclonus, caused by a previous SARS-CoV-2-infection, shortly after vaccination suggests a renewed auto-immune mediated crossreaction of antibodies to both viral epitopes and central nervous system components. Thunderclap headache after vaccination suggests a similar pathophysiological mechanism to the headache and other flu-like symptoms described after vaccination against other viruses. This might be ascribed to the activation of immunoinflammatory mediators or accompanying fever. Although headache accompanied by encephalopathy and focal neurological deficit might occur as part of a cytokine release syndrome, this is clinically less likely.ConclusionsA variety of symptoms, including thunderclap headache, focal deficits and movement disorders, can occur after SARS-CoV-2 vaccination, and an activation or reactivation of the immune system is suggested as most likely cause. However, one should be careful about claiming a direct correlation. It remains important to exclude other causes, such as structural lesions, infections or subarachnoid hemorrhage, and future research is required to understand possible pathophysiological mechanisms and associations with the SARS-CoV-2 vaccine.

Neuroprotection and neuroregeneration: roles for the white matter.

Efficient strategies for neuroprotection and repair are still an unmet medical need for neurodegenerative diseases and lesions of the central nervous system. Over the last few decades, a great deal of attention has been focused on white matter as a potential therapeutic target, mainly due to the discovery of the oligodendrocyte precursor cells in the adult central nervous system, a cell type able to fully repair myelin damage, and to the development of advanced imaging techniques to visualize and measure white matter lesions. The combination of these two events has greatly increased the body of research into white matter alterations in central nervous system lesions and neurodegenerative diseases and has identified the oligodendrocyte precursor cell as a putative target for white matter lesion repair, thus indirectly contributing to neuroprotection. This review aims to discuss the potential of white matter as a therapeutic target for neuroprotection in lesions and diseases of the central nervous system. Pivot conditions are discussed, specifically multiple sclerosis as a white matter disease; spinal cord injury, the acute lesion of a central nervous system component where white matter prevails over the gray matter, and Alzheimer’s disease, where the white matter was considered an ancillary component until recently. We first describe oligodendrocyte precursor cell biology and developmental myelination, and its regulation by thyroid hormones, then briefly describe white matter imaging techniques, which are providing information on white matter involvement in central nervous system lesions and degenerative diseases. Finally, we discuss pathological mechanisms which interfere with myelin repair in adulthood.

Neuronal regeneration: Vertebrates comparative overview and new perspectives for neurodegenerative diseases

AbstractNeurodegenerative diseases afflict a significant percentage of the world's population. The human nervous system is unable to regenerate after an insult, or due to senility, while low vertebrates still exhibit this ability. Comparative neurobiology can increase knowledge about neuronal degeneration and regeneration. Anamni vertebrates retain the ability to regenerate up to large areas of the nervous system. The regenerative ability of central nervous system components depends on the phylogenetic distance between classes of vertebrates. It decreases during evolution. Teleosts can skilfully regenerate brain, spinal cord and retina. Amphibians and reptiles can only regenerate certain areas; spinal cord regeneration in reptiles is limited to axonal regrowth. Retina regeneration is possible in bird embryo but not in the adult. In this review, we analyse how the regeneration of neurons occurs in different classes of vertebrates, and how the study of these mechanisms could be applied to the search for new therapies for neurodegenerative disorders.