Types Of Glia Research Articles

Toluene Toxicity in the Brain: From Cellular Targets to Molecular Mechanisms.

Toluene intoxication constitutes a persistent public health problem worldwide. While most organs can be damaged, the brain is a primary target whether exposure is accidental, occupational, or recreational. Interventions to prevent/revert brain damage by toluene are curtailed by the scarce information on the molecular targets and mechanisms mediating toluene's brain toxicity and the common exposure to other neurotoxins and/or coexistence of neurological/psychiatric disorders. We examine (a) the physicochemical properties of toluene that allow this inhalant to primarily target the lipid-rich brain; (b) the cell types targeted by toluene (neurons, different types of glia), while considering a cerebrovascular component; and (c) putative molecular mechanisms by which toluene may modify receptor function while analyzing structural features that allow toluene to directly interact with membrane lipids or specific proteins. This information constitutes a stepping stone to design pharmacotherapies that counteract toluene brain intoxication.

Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis.

Brain water homeostasis not only provides a physical protection, but also determines the diffusion of chemical molecules key for information processing and metabolic stability. As a major type of glia in brain parenchyma, astrocytes are the dominant cell type expressing aquaporin water channel. How astrocyte aquaporin contributes to brain water homeostasis in basal physiology remains to be understood. We report that astrocyte aquaporin 4 (AQP4) mediates a tonic water efflux in basal conditions. Acute inhibition of astrocyte AQP4 leads to intracellular water accumulation as optically resolved by fluorescence-translated imaging in acute brain slices, and in vivo by fiber photometry in mobile mice. We then show that aquaporin-mediated constant water efflux maintains astrocyte volume and osmotic equilibrium, astrocyte and neuron Ca2+ signaling, and extracellular space remodeling during optogenetically induced cortical spreading depression. Using diffusion-weighted magnetic resonance imaging (DW-MRI), we observed that in vivo inhibition of AQP4 water efflux heterogeneously disturbs brain water homeostasis in a region-dependent manner. Our data suggest that astrocyte aquaporin, though bidirectional in nature, mediates a tonic water outflow to sustain cellular and environmental equilibrium in brain parenchyma.

Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis

Brain water homeostasis not only provides a physical protection, but also determines the diffusion of chemical molecules key for information processing and metabolic stability. As a major type of glia in brain parenchyma, astrocytes are the dominant cell type expressing aquaporin water channel. How astrocyte aquaporin contributes to brain water homeostasis in basal physiology remains to be understood. We report that astrocyte aquaporin 4 (AQP4) mediates a tonic water efflux in basal conditions. Acute inhibition of astrocyte AQP4 leads to intracellular water accumulation as optically resolved by fluorescence-translated imaging in acute brain slices, and in vivo by fiber photometry in mobile mice. We then show that aquaporin-mediated constant water efflux maintains astrocyte volume and osmotic equilibrium, astrocyte and neuron Ca2+ signaling, and extracellular space remodeling during optogenetically induced cortical spreading depression. Using diffusion-weighted magnetic resonance imaging (DW-MRI), we observed that in vivo inhibition of AQP4 water efflux heterogeneously disturbs brain water homeostasis in a region-dependent manner. Our data suggest that astrocyte aquaporin, though bidirectional in nature, mediates a tonic water outflow to sustain cellular and environmental equilibrium in brain parenchyma.

Molecular-genetic markers of neuroglia in traumatic brain injury and their use for assessing functional status of sportsmen

Neuroglia performs multiple important functions including maintaining brain homeostasis, metabolism, neuroprotection and modulating neurotransmission. Studying the role of neuroglia is necessary to understand the development of pathological neurodegenerative processes, as well as the restoration of nervous tissue during inflammation or injury. However, the analysis of neuroglial processes is complicated by its high heterogeneity and the lack of a system of biomarkers that make it possible to unambiguously assess the functional state of the nervous system. Here, we analyze data on clinically significant molecular genetic markers of different types of neuroglia, and the prospects for their use in sport physiology, including the assessment of athletes following traumatic brain injuries of varying severity and other types of sport-related traumas.

Mapping the glial transcriptome in Huntington’s disease using snRNAseq: selective disruption of glial signatures across brain regions

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.

The Organism as the Niche: Physiological States Crack the Code of Adult Neural Stem Cell Heterogeneity.

Neural stem cells (NSCs) persist in the adult mammalian brain and are able to give rise to new neurons and glia throughout life. The largest stem cell niche in the adult mouse brain is the ventricular-subventricular zone (V-SVZ) lining the lateral ventricles. Adult NSCs in the V-SVZ coexist in quiescent and actively proliferating states, and they exhibit a regionalized molecular identity. The importance of such spatial diversity is just emerging, as depending on their position within the niche, adult NSCs give rise to distinct subtypes of olfactory bulb interneurons and different types of glia. However, the functional relevance of stem cell heterogeneity in the V-SVZ is still poorly understood. Here, we put into perspective findings highlighting the importance of adult NSC diversity for brain plasticity, and how the body signals to brain stem cells in different physiological states to regulate their behavior.

Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.

Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.

Embryonic spatiotemporal expression pattern of Folded gastrulation suggests roles in multiple morphogenetic events and regulation by AbdA.

In Drosophila, the signaling pathway activated by the ligand Folded gastrulation (Fog) is among the few known G protein-coupled receptor (GPCR) pathways to regulate cell shape change with a well-characterized role in gastrulation. However, an understanding of the spectrum of morphogenetic events regulated by Fog signaling is still lacking. Here, we present an analysis of the expression pattern and regulation of fog using a genome-engineered Fog::sfGFP line. We show that Fog expression is widespread and in tissues previously not associated with the signaling pathway including germ cells, trachea, and amnioserosa. In the central nervous system (CNS), we find that the ligand is expressed in multiple types of glia indicating a prominent role in the development of these cells. Consistent with this, we have identified 3 intronic enhancers whose expression in the CNS overlaps with Fog::sfGFP. Further, we show that enhancer-1, (fogintenh-1) located proximal to the coding exon is responsive to AbdA. Supporting this, we find that fog expression is downregulated in abdA mutants. Together, our study highlights the broad scope of Fog-GPCR signaling during embryogenesis and identifies Hox gene AbdA as a novel regulator of fog expression.

Pathological changes of glial cells in the enteric nervous system of the colon with chronic slow-transit constipation

The origin, development and differentiation of enteric nervous system neuroglia and its involvement in the pathogenesis of gastrointestinal diseases and neurodegenerative diseases have been little studied.Aim of this work is a comparative morphological study of glial cells in the ganglionic plexuses of the enteric nervous system and analysis of neuroglial relationships in chronic slow-transit constipation using immunohistochemical methods.Material and methods. Resection material obtained at the Department of Faculty Surgery, S.P. Fedorov Faculty of Surgery of S.M. Kirov Military Medical Academy during planned surgical operations was used. The objects of the study were fragments of the sigmoid and colon obtained as a result of surgery for chronic slow-transit constipation (five cases, women aged 37–40 years). The study was carried out using immunohistochemical glial markers (GFAP, S100β protein, etc.).Results. Two types of glia were found in the myenteric ganglionic plexus of the large intestine: astrocyte-like and neurolemmocytic. The astrocyte-like type is similar to the neuroglia of the central nervous system, the neurolemmocytic type is similar to the glia of the autonomic nervous system. It has been established that astrocyte-like glia is found only in the Aauerbach ganglionic plexus, while neurolemmocytes are found in all innervated tissues of the intestinal wall. Reactive, dystrophic and degenerative changes in neurocytes, glial elements, agangliogenosis in the Auerbach plexus were found in all cases of chronic slow-transit constipation. Destructive changes in the neuromuscular terminal plexuses, interstitial edema and inflammatory monocytic reaction and leukocyte infiltration in the intestinal mucosa and intestinal submucosa, found in several cases.Conclusions. The results obtained allow classifying chronic slow-transit constipation as a neurodegenerative disease.

A machine learning method to explore the glymphatic system via poroelastodynamics

Until recently, scientists thought that waste was cleared from the central nervous system primarily by diffusion, with waste slowly moving from the brain tissue toward the blood vessels. However, scientists have discovered a dedicated macroscopic waste clearance system, called glymphatic system, that performs efficient waste elimination through a unique system of perivascular channels formed by astrocytes, a type of glia. To better understand the complex dynamics of fluid movements in the glymphatic system, we implemented a four-compartmental poroelasticity model of the cerebral environment and used the model in a systematic and efficient parametric study aided by machine learning, a physiologically inspired perceptron method, to explore the functional impact of water transfer coefficients. The results suggested that the model captured the transport phenomenon of human brain. Moreover, within a specific distribution range of water transfer coefficients, the model indirectly predicts the existence of the glymphatic system, providing theoretical support to the glymphatic theory. Our study also demonstrates the feasibility of discovering physiological properties of complex biological systems through computer-aided modeling. Meanwhile, the presented novel method shown its potential for parametric study.

Echinoderm radial glia in adult cell renewal, indeterminate growth, and regeneration.

Echinoderms are a phylum of marine deterostomes with a range of interesting biological features. One remarkable ability is their impressive capacity to regenerate most of their adult tissues, including the central nervous system (CNS). The research community has accumulated data that demonstrates that, in spite of the pentaradial adult body plan, echinoderms share deep similarities with their bilateral sister taxa such as hemichordates and chordates. Some of the new data reveal the complexity of the nervous system in echinoderms. In terms of the cellular architecture, one of the traits that is shared between the CNS of echinoderms and chordates is the presence of radial glia. In chordates, these cells act as the main progenitor population in CNS development. In mammals, radial glia are spent in embryogenesis and are no longer present in adults, being replaced with other neural cell types. In non-mammalian chordates, they are still detected in the mature CNS along with other types of glia. In echinoderms, radial glia also persist into the adulthood, but unlike in chordates, it is the only known glial cell type that is present in the fully developed CNS. The echinoderm radial glia is a multifunctional cell type. Radial glia forms the supporting scaffold of the neuroepithelium, exhibits secretory activity, clears up dying or damaged cells by phagocytosis, and, most importantly, acts as a major progenitor cell population. The latter function is critical for the outstanding developmental plasticity of the adult echinoderm CNS, including physiological cell turnover, indeterminate growth, and a remarkable capacity to regenerate major parts following autotomy or traumatic injury. In this review we summarize the current knowledge on the organization and function of the echinoderm radial glia, with a focus on the role of this cell type in adult neurogenesis.

The role of glial autophagy in Alzheimer's disease.

Although Alzheimer's disease is the most pervasive neurodegenerative disorder, the mechanism underlying its development is still not precisely understood. Available data indicate that pathophysiology of this disease may involve impaired autophagy in glial cells. The dysfunction is manifested as reduced ability of astrocytes and microglia to clear abnormal protein aggregates. Consequently, excessive accumulation of amyloid beta plaques and neurofibrillary tangles activates microglia and astrocytes leading to decreased number of mature myelinated oligodendrocytes and death of neurons. These pathologic effects of autophagy dysfunction can be rescued by pharmacological activation of autophagy. Therefore, a deeper understanding of the molecular mechanisms involved in autophagy dysfunction in glial cells in Alzheimer's disease may lead to the development of new therapeutic strategies. However, such strategies need to take into consideration differences in regulation of autophagy in different types of neuroglia.

Calcium signaling in astrocytes and gliotransmitter release.

Glia are as numerous in the brain as neurons and widely known to serve supportive roles such as structural scaffolding, extracellular ionic and neurotransmitter homeostasis, and metabolic support. However, over the past two decades, several lines of evidence indicate that astrocytes, which are a type of glia, play active roles in neural information processing. Astrocytes, although not electrically active, can exhibit a form of excitability by dynamic changes in intracellular calcium levels. They sense synaptic activity and release neuroactive substances, named gliotransmitters, that modulate neuronal activity and synaptic transmission in several brain areas, thus impacting animal behavior. This "dialogue" between astrocytes and neurons is embodied in the concept of the tripartite synapse that includes astrocytes as integral elements of synaptic function. Here, we review the recent work and discuss how astrocytes via calcium-mediated excitability modulate synaptic information processing at various spatial and time scales.

Establishment of an in vitro Differentiation and Dedifferentiation System of Rat Schwann Cells.

In the peripheral nervous system, Schwann cells are the primary type of glia; their in vitro differentiation and dedifferentiation system has not been described in detail in the literature. Thus, an in vitro differentiation and dedifferentiation system of rat Schwann cells is described in this protocol. These cultures and systems may be used to investigate the morphological and biochemical effects of drug interventions or lentivirus-mediated gene transfer on Schwann cells during differentiation or dedifferentiation. Graphical abstract.

Molecular basis of astrocyte diversity and morphology across the CNS in health and disease.

Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, and morphology across the mouse central nervous system (CNS). We identified shared and region-specific astrocytic genes and functions and explored the cellular origins of their regional diversity. We identified gene networks correlated with astrocyte morphology, several of which unexpectedly contained Alzheimer's disease (AD) risk genes. CRISPR/Cas9-mediated reduction of candidate genes reduced astrocyte morphological complexity and resulted in cognitive deficits. The same genes were down-regulated in human AD, in an AD mouse model that displayed reduced astrocyte morphology, and in other human brain disorders. We thus provide comprehensive molecular data on astrocyte diversity and mechanisms across the CNS and on the molecular basis of astrocyte morphology in health and disease.

The Role of Glia Clocks in the Regulation of Sleep in Drosophila melanogaster.

In Drosophila melanogaster, the pacemaker located in the brain plays the main role in maintaining circadian rhythms; however, peripheral oscillators including glial cells, are also crucial components of the circadian network. In the present study, we investigated an impact of oscillators located in astrocyte-like glia, the chiasm giant glia of the optic lobe, epithelial and subperineurial glia on sleep of Drosophila males. We described that oscillators located in astrocyte-like glia and chiasm giant glia are necessary to maintain daily changes in clock neurons arborizations, while those located in epithelial glia regulate amplitude of these changes. Finally, we showed that communication between glia and neurons through tripartite synapses formed by epithelial glia and, in effect, neurotransmission regulation plays important role in wake-promoting during the day.SIGNIFICANCE STATEMENT Circadian clock or pacemaker regulates many aspects of animals' physiology and behavior. The pacemaker is located in the brain and is composed of neurons. However, there are also additional oscillators, called peripheral clocks, which synchronize the main clock. Despite the critical role of glia in the clock machinery, little is known which type of glia houses peripheral oscillators and how they affect neuronal clocks. This study using Drosophila shows that oscillators in specific glia types maintain awakeness during the day by regulating the daily plasticity of clock neurons.

Sex-Specific Transcriptomic Signatures in Brain Regions Critical for Neuropathic Pain-Induced Depression.

Neuropathic pain is a chronic debilitating condition with a high comorbidity with depression. Clinical reports and animal studies have suggested that both the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC) are critically implicated in regulating the affective symptoms of neuropathic pain. Neuropathic pain induces differential long-term structural, functional, and biochemical changes in both regions, which are thought to be regulated by multiple waves of gene transcription. However, the differences in the transcriptomic profiles changed by neuropathic pain between these regions are largely unknown. Furthermore, women are more susceptible to pain and depression than men. The molecular mechanisms underlying this sexual dimorphism remain to be explored. Here, we performed RNA sequencing and analyzed the transcriptomic profiles of the mPFC and ACC of female and male mice at 2 weeks after spared nerve injury (SNI), an early time point when the mice began to show mild depressive symptoms. Our results showed that the SNI-induced transcriptomic changes in female and male mice were largely distinct. Interestingly, the female mice exhibited more robust transcriptomic changes in the ACC than male, whereas the opposite pattern occurred in the mPFC. Cell type enrichment analyses revealed that the differentially expressed genes involved genes enriched in neurons, various types of glia and endothelial cells. We further performed gene set enrichment analysis (GSEA), which revealed significant de-enrichment of myelin sheath development in both female and male mPFC after SNI. In the female ACC, gene sets for synaptic organization were enriched, and gene sets for extracellular matrix were de-enriched after SNI, while such signatures were absent in male ACC. Collectively, these findings revealed region-specific and sexual dimorphism at the transcriptional levels induced by neuropathic pain, and provided novel therapeutic targets for chronic pain and its associated affective disorders.

Role of Extracellular Vesicles in Glia-Neuron Intercellular Communication.

Cross talk between glia and neurons is crucial for a variety of biological functions, ranging from nervous system development, axonal conduction, synaptic transmission, neural circuit maturation, to homeostasis maintenance. Extracellular vesicles (EVs), which were initially described as cellular debris and were devoid of biological function, are now recognized as key components in cell-cell communication and play a critical role in glia-neuron communication. EVs transport the proteins, lipids, and nucleic acid cargo in intercellular communication, which alters target cells structurally and functionally. A better understanding of the roles of EVs in glia-neuron communication, both in physiological and pathological conditions, can aid in the discovery of novel therapeutic targets and the development of new biomarkers. This review aims to demonstrate that different types of glia and neuronal cells secrete various types of EVs, resulting in specific functions in intercellular communications.

The relationships between neuroglial alterations and neuronal changes in Alzheimer's disease, and the related controversies I: Gliopathogenesis and glioprotection.

Since Alois Alzheimer described the pathology of Alzheimer’s disease in 1907, an increasing number of studies have attempted to discover its causes and possible ways to treat it. For decades, research has focused on neuronal degeneration and the disruption to the neural circuits that occurs during disease progression, undervaluing in some extent the alterations to glial cells even though these alterations were described in the very first studies of this disease. In recent years, it has been recognized that different families of neuroglia are not merely support cells for neurons but rather key and active elements in the physiology and pathology of the nervous system. Alterations to different types of neuroglia (especially astroglia and microglia but also mature oligodendroglia and oligodendroglial progenitors) have been identified in the initial neuropathological changes that lead to dementia, suggesting that they may represent therapeutic targets to prevent neurodegeneration. In this review, based on our own studies and on the relevant scientific literature, we argue that a careful and in-depth study of glial cells will be fundamental to understanding the origin and progression of Alzheimer’s disease. In addition, we analyze the main issues regarding the neuroprotective and neurotoxic role of neuroglial changes, reactions and/or involutions in both humans with Alzheimer’s disease and in experimental models of this condition.

Ferroptosis in Parkinson's disease: glia-neuron crosstalk.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.