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Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The unquestionable clinical impact of Bioelectronic Medicine is underscored by the successful translation to humans in the last decades, and the long list of preclinical studies. Given the emergency of accelerating the progress in new neuromodulation treatments (i.e., drug-resistant hypertension, autoimmune and degenerative diseases), collaboration between multiple fields is imperative. This work intends to foster multidisciplinary work and bring together different fields to provide the fundamental basis underlying Bioelectronic Medicine. In this review we will go from the biophysics of the cell membrane, which we consider the inner core of neuromodulation, to patient care. We will discuss the recently discovered mechanism of neurotransmission switching and how it will impact neuromodulation design, and we will provide an update on neuronal and glial basis in health and disease. The advances in biomedical technology have facilitated the collection of large amounts of data, thereby introducing new challenges in data analysis. We will discuss the current approaches and challenges in high throughput data analysis, encompassing big data, networks, artificial intelligence, and internet of things. Emphasis will be placed on understanding the electrochemical properties of neural interfaces, along with the integration of biocompatible and reliable materials and compliance with biomedical regulations for translational applications. Preclinical validation is foundational to the translational process, and we will discuss the critical aspects of such animal studies. Finally, we will focus on the patient point-of-care and challenges in neuromodulation as the ultimate goal of bioelectronic medicine. This review is a call to scientists from different fields to work together with a common endeavor: accelerate the decoding and modulation of the nervous system in a new era of therapeutic possibilities.

Synaptic communication is an important process in the central nervous system that allows for the rapid and spatially specified transfer of signals. Neurons receive various synaptic inputs and generate action potentials required for information transfer, and these inputs can be excitatory or inhibitory, which collectively determines the output. Non-neuronal cells (glial cells) have been identified as crucial participants in influencing neuronal activity and synaptic transmission, with astrocytes forming tripartite synapses and microglia pruning synapses. While it has been known that oligodendrocyte precursor cells (OPCs) receive neuronal inputs, whether they also influence neuronal activity and synaptic transmission has remained unknown for two decades. Recent findings indicate that OPCs, too, modulate neuronal synapses. In this review, we discuss the roles of different glial cell types at synapses, including the recently discovered involvement of OPCs in synaptic transmission and synapse refinement, and discuss overlapping roles played by multiple glial cell types. [ABSTRACT FROM AUTHOR]

Despite increasing in mass approximately 100-fold during larval life, the Drosophila CNS maintains its characteristic form. Dynamic interactions between the overlying basement membrane and underlying surface glia are known to regulate CNS structure in Drosophila , but the genes and pathways that establish and maintain CNS morphology during development remain poorly characterized. To identify genes that regulate CNS shape in Drosophila , we conducted an EMS-based, forward genetic screen of the second chromosome, uncovered 50 mutations that disrupt CNS structure, and mapped these alleles to 17 genes. Analysis of whole genome sequencing data wedded to genetic studies uncovered the affected gene for all but 1 mutation. Identified genes include well-characterized regulators of tissue shape, like LanB1 , viking , and Collagen type IV alpha1 , and previously characterized genes, such as Toll-2 and Rme-8 , with no known role in regulating CNS structure. We also uncovered that papilin and C1GalTA likely act in the same pathway to regulate CNS structure and found that the fly homolog of a glucuronosyltransferase, B4GAT1/LARGE1, that regulates Dystroglycan function in mammals is required to maintain CNS shape in Drosophila. Finally, we show that the senseless-2 transcription factor is expressed and functions specifically in surface glia found on peripheral nerves but not in the CNS to govern CNS structure, identifying a gene that functionally subdivides a glial subtype along the peripheral–central axis. Future work on these genes should clarify the genetic mechanisms that ensure the homeostasis of CNS form during development. [ABSTRACT FROM AUTHOR]

Neuroinflammation is considered to be one of the driving factors in Parkinson's disease (PD). This study was conducted using neuronal and glial cell cultures differentiated from induced pluripotent stem cells (iPSC) of healthy donors (HD) and PD patients with different PARK2 mutations (PD). Based on the results of RNA sequencing, qPCR and ELISA, we revealed transcriptional and post-transcriptional changes in HD and PD neurons cultivated in HD and PD glial-conditioned medium. We demonstrated that if one or both of the components of the system, neurons or glia, is Parkin-deficient, the interaction resulted in the down-regulation of a number of key genes related to inflammatory intracellular pathways and negative regulation of apoptosis in neurons, which might be neuroprotective. In PD neurons, the stress-induced up-regulation of APLNR was significantly stronger compared to HD neurons and was diminished by glial soluble factors, both HD and PD. PD neurons in PD glial conditioned medium increased APLN expression and also up-regulated apelin synthesis and release into intracellular fluid, which represented another compensatory action. Overall, the reported results indicate that neuronal self-defense mechanisms contribute to cell survival, which might be characteristic of PD patients with Parkin-deficiency. [ABSTRACT FROM AUTHOR]

The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein involved in the biosynthesis of iron-sulfur clusters. We previously reported that Tspo was overexpressed in a Drosophila model of this disease generated by CRISPR/Cas9 insertion of approximately 200 GAA in the intron of fh , the fly frataxin gene. Here, we describe a new Drosophila model of FA with 42 GAA repeats, called fh-GAAs. The smaller expansion size allowed to obtain adults exhibiting hallmarks of the FA disease, including short lifespan, locomotory defects and hypersensitivity to oxidative stress. The reduced lifespan was fully rescued by ubiquitous expression of human FXN , confirming that both frataxins share conserved functions. We observed that Tspo was overexpressed in heads and decreased in intestines of these fh-GAAs flies. Then, we further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context. • A 42 GAA-based Drosophila model of Friedreich Ataxia exhibit hallmarks of the disease. • Overexpression of Tspo in glial cells improves survival of frataxin-deficient flies. • Glial but not neuron-specific overexpression of Tspo increases Drosophila lifespan. [ABSTRACT FROM AUTHOR]

Following peripheral nerve damage, various non-neuronal cells are activated, triggering accumulation in the peripheral and central nervous systems, and communicate with neurons. Evidence suggest that neuronal and non-neuronal cell communication is a critical mechanism of neuropathic pain; however, its detailed mechanisms in contributing to neuropathic orofacial pain development remain unclear. Neuronal and non-neuronal cell communication in the trigeminal ganglion (TG) is believed to cause neuronal hyperactivation following trigeminal nerve damage, resulting in neuropathic orofacial pain. Trigeminal nerve damage activates and accumulates non-neuronal cells, such as satellite cells and macrophages in the TG and microglia, astrocytes, and oligodendrocytes in the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1–C2). These non-neuronal cells release various molecules, contributing to the hyperactivation of TG, Vc, and C1–C2 nociceptive neurons. These hyperactive nociceptive neurons release molecules that enhance non-neuronal cell activation. This neuron and non-neuronal cell crosstalk causes hyperactivation of nociceptive neurons in the TG, Vc, and C1–C2. Here, we addressed previous and recent data on the contribution of neuronal and non-neuronal cell communication and its involvement in neuropathic orofacial pain development. Previous and recent data suggest that neuronal and non-neuronal cell communication in the TG, Vc, and C1–C2 is a key mechanism that causes neuropathic orofacial pain associated with trigeminal nerve damage. [ABSTRACT FROM AUTHOR]

The selection of experimental specimens is critical for elucidating brain function. Specimens used in brain research range from in vivo (individual level) to in vitro (culture level). Recently, in vivo research has been particularly popular, considered an ideal experimental system for observing brain functions in real time and elucidating physiological functions without harming individuals. However, in vivo specimens, which form complex neural circuits, also have drawbacks, including 1) difficulty in data analysis and interpretation of phenomena ; 2) limitations in experimental manipulation and control of neural circuits ; 3) the number of cases cannot be easily obtained due to the required skill in conducting experiments ; and 4) animal welfare issues. On the other hand, an in vitro model introduced in this issue offers the advantage of artificially simplifying the model, enabling a more precise and accurate analysis of brain functions in vitro. This paper presents an autapse culture preparation using single neurons. [ABSTRACT FROM AUTHOR]

Myelin-forming oligodendrocytes in the vertebrate nervous system co-express the transcription factor Sox10 and its paralog Sox8. While Sox10 plays crucial roles throughout all stages of oligodendrocyte development, including terminal differentiation, the loss of Sox8 results in only mild and transient perturbations. Here, we aimed to elucidate the roles and interrelationships of these transcription factors in fully differentiated oligodendrocytes and myelin maintenance in adults. For that purpose, we conducted targeted deletions of Sox10, Sox8, or both in the brains of two-month-old mice. Three weeks post-deletion, none of the resulting mouse mutants exhibited significant alterations in oligodendrocyte numbers, myelin sheath counts, myelin ultrastructure, or myelin protein levels in the corpus callosum, despite efficient gene inactivation. However, differences were observed in the myelin gene expression in mice with Sox10 or combined Sox8/Sox10 deletion. RNA-sequencing analysis on dissected corpus callosum confirmed substantial alterations in the oligodendrocyte expression profile in mice with combined deletion and more subtle changes in mice with Sox10 deletion alone. Notably, Sox8 deletion did not affect any aspects of the expression profile related to the differentiated state of oligodendrocytes or myelin integrity. These findings extend our understanding of the roles of Sox8 and Sox10 in oligodendrocytes into adulthood and have important implications for the functional relationship between the paralogs and the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Despite widespread use of combination antiretroviral therapy (cART), there remains a subset of individuals who display cognitive impairment broadly known as HIV‐associated neurocognitive disorder (HAND). Interestingly, HIV‐infected cells continuously release the HIV‐1 protein Tat even in the presence of cART. Persistent exposure to Tat is proposed to increase both neuroinflammation and neurotoxicity. In vitro evidence shows that matrix metalloproteinases (MMPs) are among the neuroinflammatory molecules induced by Tat, which are known to disrupt specialized neuronal extracellular matrix structures called perineuronal nets (PNNs). PNNs predominantly surround parvalbumin interneurons and help to buffer these cells from oxidant stress and to independently increase their excitability. In order to better understand the link between short‐term exposure to Tat, neuroinflammation, and PNNs, we explored the direct effects of Tat on glial cells and neurons. Herein, we report that in mixed glial cultures, Tat directly increases the expression of proinflammatory molecules, including MMP‐9. Moreover, direct injection of Tat protein into mouse hippocampus increases the expression of astrocyte and microglia markers as well as MMP‐9. The number of PNNs is decreased following Tat exposure, followed later by decreased numbers of hippocampal parvalbumin‐expressing neurons. In older mice, Tat induced significant increases in the gene expression of proinflammatory molecules including markers of gliosis, MMPs and complement system proteins. Taken together, these data support a direct effect of Tat on glial‐derived MMP expression subsequently affecting PNNs and neuronal health, with older mice more susceptible to Tat‐induced inflammation. [ABSTRACT FROM AUTHOR]

The central control of energy homeostasis is a regulatory axis that involves the sensing of nutrients, signaling molecules, adipokines, and neuropeptides by neurons in the metabolic centers of the hypothalamus. However, non-neuronal glial cells are also abundant in the hypothalamus and recent findings have underscored the importance of the metabolic crosstalk and horizontal lipid flux between glia and neurons to the downstream regulation of systemic metabolism. New transgenic models and high-resolution analyses of glial phenotype and function have revealed that glia sit at the nexus between lipid metabolism and neural function, and may markedly impact the brain's response to dietary lipids or the supply of brain-derived lipids. Glia comprise the main cellular compartment involved in lipid synthesis, lipoprotein production, and lipid processing in the brain. In brief, tanycytes provide an interface between peripheral lipids and neurons, astrocytes produce lipoproteins that transport lipids to neurons and other glia, oligodendrocytes use brain-derived and dietary lipids to myelinate axons and influence neuronal function, while microglia can remove unwanted lipids in the brain and contribute to lipid re-utilization through cholesterol efflux. Here, we review recent findings regarding glial-lipid transport and highlight the specific molecular factors necessary for lipid processing in the brain, and how dysregulation of glial-neuronal metabolic crosstalk contributes to imbalanced energy homeostasis. Furthering our understanding of glial lipid metabolism will guide the design of future studies that target horizontal lipid processing in the brain to ameliorate the risk of developing obesity and metabolic disease. • Lipid processing in the brain involves metabolic crosstalk and horizontal lipid flux between neurons and non-neuronal glia. • Disruption of this complex neuron-glia interplay has effects on neuronal function, and systemic energy balance. • Exposure to high-fat diets cause a shift towards a more inflammatory glial phenotype and away from metabolic support. • Sexual dimorphism in glial metabolism and phenotype could contribute to metabolic disease susceptibility. [ABSTRACT FROM AUTHOR]

[Display omitted] • Both HIIT and MICT improved PIA-induced depression and anxiety by inhibiting glial activation. • HIIT was superior to MICT in alleviating anxiety-like and depresive-like behaviors in PIA mice. • HIIT ameliorated PIA-induced abnormalities and increases glia-derived IL-4 and BDNF release by specifically regulating KDM6B. Postnatal immune activation (PIA) induces persistent glial activation in the brain and causes various neuropathologies in adults. Exercise training improves stress-related mood disorders; however, the role of exercise in psychiatric disorders induced by early-life immune activation and the association between exercise training and glial activation remain unclear. We compared the effects of different exercise intensities on the PIA model, including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Both HIIT and MICT in adolescent mice inhibited neuroinflammation, remodeled synaptic plasticity, and improved PIA-induced mood disorders in adulthood. Importantly, HIIT was superior to MICT in terms of reducing inflammation and increasing body weight. RNA-seq of prefrontal cortex (PFC) tissues revealed a gene expression pattern, confirming that HIIT was more effective than MICT in improving brain glial cell activation through epigenetic modifications of KDM6B. We investigated the role of KDM6B, a specific histone lysine demethylation enzyme — histone 3 lysine 27 demethylase, in inhibiting glial activation against PIA-induced depression and anxiety by regulating the expression of IL-4 and brain-derived neurotrophic factor (BDNF). Overall, our data support the idea that HIIT improves PIA-induced mood disorders by regulating KDM6B-mediated epigenetic mechanisms and indicate that HIIT might be superior to MICT in improving mood disorders with PIA in mice. Our findings provide new insights into the treatment of anxiety and depression disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a condition in the brain that is marked by a gradual and ongoing reduction in memory, thought, and the ability to perform simple tasks. AD has a poor prognosis but no cure yet. Therefore, the need for novel models to study its pathogenesis and therapeutic strategies is evident, as the brain poorly recovers after injury and neurodegenerative diseases and can neither replace dead neurons nor reinnervate target structures. Recently, mesenchymal stem cells (MSCs), particularly those from the human olfactory mucous membrane referred to as the olfactory ecto-MSCs (OE-MSCs), have emerged as a potential avenue to explore in modeling AD and developing therapeutics for the disease due to their lifelong regeneration potency and facile accessibility. This review provides a comprehensive summary of the current literature on isolating OE-MSCs and delves into whether they could be reliable models for studying AD pathogenesis. It also explores whether healthy individual-derived OE-MSCs could be therapeutic agents for the disease. Despite being a promising tool in modeling and developing therapies for AD, some significant issues remain, which are also discussed in the review. [ABSTRACT FROM AUTHOR]

Maintaining the telomere length is decisive for the viability and homeostasis process of all the cells of an organism, including human glial cells. Telomere shortening of microglial cells has been widely associated with the onset and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Additionally, traumatic brain injury appears to have a positive correlation with the telomere-shortening process of microglia, and telomere length can be used as a non-invasive biomarker for the clinical management of these patients. Moreover, telomere involvement through telomerase reactivation and homologous recombination also known as the alternative lengthening of telomeres (ALT) has been described in gliomagenesis pathways, and particular focus has been given in the translational significance of these mechanisms in gliomas diagnosis and prognostic classification. Finally, glia telomere shortening is implicated in some psychiatric diseases. Given that telomere dysfunction of glial cells is involved in the central nervous system (CNS) disease pathogenesis, it represents a promising drug target that could lead to the incorporation of new tools in the medicinal arsenal for the management of so far incurable conditions. [ABSTRACT FROM AUTHOR]

Purpose: Gene‐expression reporter systems, such as green fluorescent protein, have been instrumental to understanding biological processes in living organisms at organ system, tissue, cell, and molecular scales. More than 30 years of work on developing MRI‐visible gene‐expression reporter systems has resulted in a variety of clever application‐specific methods. However, these techniques have not yet been widely adopted, so a general‐purpose expression reporter is still required. Here, we demonstrate that the manganese ion transporter Zip14 is an in vivo MRI‐visible, flexible, and robust gene‐expression reporter to meet this need. Methods: Plasmid constructs consisting of a cell type–specific promoter, gene coding for human Zip14, and a histology‐visible tag were packaged into adeno‐associated viruses. These viruses were intracranially injected into the mouse brain. Serial in vivo MRI was performed using a vendor‐supplied 3D‐MPRAGE sequence. No additional contrast agents were administered. Animals were sacrificed after the last imaging timepoint for immunohistological validation. Results: Neuron‐specific overexpression of Zip14 produced substantial and long‐lasting changes in MRI contrast. Using appropriate viruses enabled both anterograde and retrograde neural tracing. Expression of Zip14 in astrocytes also enabled MRI of glia populations in the living mammalian brain. Conclusions: The flexibility of this system as an MRI‐visible gene‐expression reporter will enable many applications of serial, high‐resolution imaging of gene expression for basic science and therapy development. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the ATP7B gene, which are responsible for impaired copper transport in the cell, inhibition of copper binding to apoceruloplasmin, and biliary excretion. This leads to the accumulation of copper in the tissues. Copper accumulation in the CNS leads to the neurological and psychiatric symptoms of WD. Abnormalities of copper metabolism in WD are associated with impaired iron metabolism. Both of these elements are redox active and may contribute to neuropathology. It has long been assumed that among parenchymal cells, astrocytes have the greatest impact on copper and iron homeostasis in the brain. Capillary endothelial cells are separated from the neuropil by astrocyte terminal legs, putting astrocytes in an ideal position to regulate the transport of iron and copper to other brain cells and protect them if metals breach the blood–brain barrier. Astrocytes are responsible for, among other things, maintaining extracellular ion homeostasis, modulating synaptic transmission and plasticity, obtaining metabolites, and protecting the brain against oxidative stress and toxins. However, excess copper and/or iron causes an increase in the number of astrocytes and their morphological changes observed in neuropathological studies, as well as a loss of the copper/iron storage function leading to macromolecule peroxidation and neuronal loss through apoptosis, autophagy, or cuproptosis/ferroptosis. The molecular mechanisms explaining the possible role of glia in copper- and iron-induced neurodegeneration in WD are largely understood from studies of neuropathology in Parkinson's disease and Alzheimer's disease. Understanding the mechanisms of glial involvement in neuroprotection/neurotoxicity is important for explaining the pathomechanisms of neuronal death in WD and, in the future, perhaps for developing more effective diagnostic/treatment methods. [ABSTRACT FROM AUTHOR]

Severe spinal cord injuries (SCI) lead to loss of functional activity of the body below the injury site, affect a person's ability to self-care and have a direct impact on performance. Due to the structural features and functional role of the spinal cord in the body, the consequences of SCI cannot be completely overcome at the expense of endogenous regenerative potential and, developing over time, lead to severe complications years after injury. Thus, the primary task of this type of injury treatment is to create artificial conditions for the regenerative growth of damaged nerve fibers through the area of the SCI. Solving this problem is possible using tissue neuroengineering involving the technology of replacing the natural tissue environment with synthetic matrices (for example, hydrogels) in combination with stem cells, in particular, neural/progenitor stem cells (NSPCs). This approach can provide maximum stimulation and support for the regenerative growth of axons of damaged neurons and their myelination. In this review, we consider the currently available options for improving the condition after SCI (use of NSC transplantation or/and replacement of the damaged area of the SCI with a matrix, specifically a hydrogel). We emphasise the expediency and effectiveness of the hydrogel matrix + NSCs complex system used for the reconstruction of spinal cord tissue after injury. Since such a complex approach (a combination of tissue engineering and cell therapy), in our opinion, allows not only to creation of conditions for supporting endogenous regeneration or mechanical reconstruction of the spinal cord, but also to strengthen endogenous regeneration, prevent the spread of the inflammatory process, and promote the restoration of lost reflex, motor and sensory functions of the injured area of spinal cord. [ABSTRACT FROM AUTHOR]

Multiple studies have demonstrated that acute ethanol consumption alters brain function and cognition. Nevertheless, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity, and recently, the opening of hemichannels has been found to play a relevant role in this process. Hemichannels are plasma membrane channels composed of six connexins or seven pannexins, respectively, that oligomerize around a central pore. They serve as ionic and molecular exchange conduits between the cytoplasm and extracellular milieu, allowing the release of various paracrine substances, such as ATP, D-serine, and glutamate, and the entry of ions and other substances, such as Ca2+ and glucose. The persistent and exacerbated opening of hemichannels has been associated with the pathogenesis and progression of several brain diseases for at least three mechanisms. The uncontrolled activity of these channels could favor the collapse of ionic gradients and osmotic balance, the release of toxic levels of ATP or glutamate, cell swelling and plasma membrane breakdown and intracellular Ca2+ overload. Here, we evaluated whether acute ethanol exposure affects the activity of astrocyte hemichannels and the possible repercussions of this phenomenon on cytoplasmatic Ca2+ signaling and gliotransmitter release. Acute ethanol exposure triggered the rapid activation of connexin43 and pannexin1 hemichannels in astrocytes, as measured by time-lapse recordings of ethidium uptake. This heightened activity derived from a rapid rise in [Ca2+]i linked to extracellular Ca2+ influx and IP3-evoked Ca2+ release from intracellular Ca2+ stores. Relevantly, the acute ethanol-induced activation of hemichannels contributed to a persistent secondary increase in [Ca2+]i. The [Ca2+]i-dependent activation of hemichannels elicited by ethanol caused the increased release of ATP and glutamate in astroglial cultures and brain slices. Our findings offer fresh perspectives on the potential mechanisms behind acute alcohol-induced brain abnormalities and propose targeting connexin43 and pannexin1 hemichannels in astrocytes as a promising avenue to prevent deleterious consequences of alcohol consumption. [ABSTRACT FROM AUTHOR]

In animal models of epilepsy, cranial surgery is often required to implant electrodes for electroencephalography (EEG) recording. However, electrode implants can lead to the activation of glial cells and interfere with physiological neuronal activity. In this study, we evaluated the impact of epidural electrode implants in the pilocarpine mouse model of temporal lobe epilepsy. Brain neuroinflammation was assessed 1 and 3 weeks after surgery by cytokines quantification, immunohistochemistry, and western blotting. Moreover, we investigated the effect of pilocarpine, administered two weeks after surgery, on mice mortality rate. The reported results indicate that implanted mice suffer from neuroinflammation, characterized by an early release of pro-inflammatory cytokines, microglia activation, and subsequent astrogliosis, which persists after three weeks. Notably, mice subjected to electrode implants displayed a higher mortality rate following pilocarpine injection 2 weeks after the surgery. Moreover, the analysis of EEGs recorded from implanted mice revealed a high number of single spikes, indicating a possible increased susceptibility to seizures. In conclusion, epidural electrode implant in mice promotes neuroinflammation that could lower the seizure thresholds to pilocarpine and increase the death rate. An improved protocol considering the persistent neuroinflammation induced by electrode implants will address refinement and reduction, two of the 3Rs principles for the ethical use of animals in scientific research. [ABSTRACT FROM AUTHOR]

Astrocytes are morphologically complex. Light microscopy reveals the structure of astrocytes at the cellular level. Volume electron microscopy is revealing the nanostructure of astrocytes. The molecular basis of astrocyte morphogenesis and complexity is emerging. Astrocytes undergo changes in morphology in diverse disease-related states. Astrocytes are predominant glial cells that tile the central nervous system (CNS). A cardinal feature of astrocytes is their complex and visually enchanting morphology, referred to as bushy, spongy, and star-like. A central precept of this review is that such complex morphological shapes evolved to allow astrocytes to contact and signal with diverse cells at a range of distances in order to sample, regulate, and contribute to the extracellular milieu, and thus participate widely in cell–cell signaling during physiology and disease. The recent use of improved imaging methods and cell-specific molecular evaluations has revealed new information on the structural organization and molecular underpinnings of astrocyte morphology, the mechanisms of astrocyte morphogenesis, and the contributions to disease states of reduced morphology. These insights have reignited interest in astrocyte morphological complexity as a cornerstone of fundamental glial biology and as a critical substrate for multicellular spatial and physiological interactions in the CNS. [ABSTRACT FROM AUTHOR]

• Neuroinflammation-related PET signal was measured in long COVID patients with diverse symptoms. • PET neuroimaging found neuroinflammation across multiple brain regions in long COVID vs. controls. • Some neuroinflammation signal was found in brain areas known to have reduced blood-brain barrier. • Neuroinflammation in Long COVID correlated with blood levels of factors related to vascular damage. The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC. [ABSTRACT FROM AUTHOR]

The transcription factor Sox10 is an important determinant of oligodendroglial identity and influences oligodendroglial development and characteristics at various stages. Starting from RNA-seq data, we here show that the expression of several voltage-gated ion channels with known expression and important function in oligodendroglial cells depends upon Sox10. These include the Nav1.1, Cav2.2, Kv1.1, and Kir4.1 channels. For each of the four encoding genes, we found at least one regulatory region that is activated by Sox10 in vitro and at the same time bound by Sox10 in vivo. Cell-specific deletion of Sox10 in oligodendroglial cells furthermore led to a strong downregulation of all four ion channels in a mouse model and thus in vivo. Our study provides a clear functional link between voltage-gated ion channels and the transcriptional regulatory network in oligodendroglial cells. Furthermore, our study argues that Sox10 exerts at least some of its functions in oligodendrocyte progenitor cells, in myelinating oligodendrocytes, or throughout lineage development via these ion channels. By doing so, we present one way in which oligodendroglial development and properties can be linked to neuronal activity to ensure crosstalk between cell types during the development and function of the central nervous system. [ABSTRACT FROM AUTHOR]

Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins. Synopsis: Hyperactivation of kinesins has been linked to neurodegenerative conditions. This study shows that a hyperactive version of OSM-3, a member of kinesin-2 superfamily that drives anterograde intraflagellar transport in C. elegans, is expelled from neurons for degradation in glial cells. Hyperactive OSM-3CA kinesin is absent from cilia and forms dynamic puncta within the neurites of sensory neurons. OSM-3CA puncta are ejected from sensory neurons and engulfed by neighboring cephalic sheath glia cells in a manner dependent of the phagocytic receptor CED-1. Mutations that reduce OSM-3CA activity or increase its microtubule binding protect OSM-3CA and restore normal cilia. ALS-linked hyperactive kinesin-1 is also expelled from neurons when ectopically expressed in C. elegans. Phagocytic receptor CED-1 enables glial uptake and subsequent degradation of hyperactive kinesins in C. elegans. [ABSTRACT FROM AUTHOR]

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimers disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-β sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.

Abstract The incidence of brain diseases in humans is increasing as we experience a worldwide ageing of the population. Treatment for such diseases is still only symptomatic as there are almost no disease-modifying therapies available. Further, since treatment often starts when symptoms appear which is only at a late stage of pathology, we need treatments that will create new cells or restore function to still living cells. Cell transplant therapy, where neuronal progenitor cells derived from stem cells are transplanted to the brain, has seen experimental success. And though there has been some clinical progress, there is still no available therapy. While through the years brain research has focused on neurons, it is now shifting to the so-called support cells of the brain, glia. In neurodegenerative diseases and stroke, glia play roles in the pathogenesis of disease. Therefore, replacing them or enhancing their functions to ultimately save or restore neurons is a new avenue of research that has gained traction in recent years. In this review, we present the current state-of-the-art on transplantation of glia cells, feasibility of this as a therapy, and upcoming directions in the field.

Teleost fish exhibit the most pronounced and widespread adult neurogenesis. Recently, functional development and the fate of newborn neurons have been reported in the optic tectum (OT) of fish. To determine the role of neurogenesis in the OT, this study used histological, immunohistochemical, and electron microscopic investigations on 18 adult Molly fish specimens (Poecilia sphenops). The OT of the Molly fish was a bilateral lobed structure located in the dorsal part of the mesencephalon. It exhibited a laminated structure made up of alternating fiber and cellular layers, which were organized into six main layers. The stratum opticum (SO) was supplied by optic nerve fibers, in which the neuropil was the main component. Radial bipolar neurons that possessed bundles of microtubules were observed in the stratum fibrosum et griseum superficiale (SFGS). Furthermore, oligodendrocytes with their processes wrapped around the nerve fibers could be observed. The stratum album centrale (SAC) consisted mainly of the axons of the stratum griseum centrale (SGC) and the large tectal, pyriform, and horizontal neurons. The neuronal cells of the SO and large tectal cells of the SAC expressed autophagy‐related protein‐5 (APG5). Interleukin‐1β (IL‐1β) was expressed in both neurons and glia cells of SGC. Additionally, inducible nitric oxide synthase (iNOS) was expressed in the neuropil of the SAC synaptic layer and granule cells of the stratum periventriculare (SPV). Also, transforming growth factor beta (TGF‐β), SRY‐box transcription factor 9 (SOX9), and myostatin were clearly expressed in the proliferative neurons. In all strata, S100 protein and Oligodendrocyte Lineage Transcription Factor 2 (Olig2) were expressed by microglia, oligodendrocytes, and astrocytes. In conclusion, it was possible to identify different varieties of neurons in the optic tectum, each with a distinct role. The existence of astrocytes, proliferative neurons, and stem cells highlights the regenerative capacity of OT. Research Highlights: The OT of the Molly fish exhibited a laminated structure made up of alternating fiber and cellular layers, which were organized into six main layers.Radial bipolar neurons that possessed bundles of microtubules were observed in the stratum fibrosum et griseum superficiale (SFGS).The stratum album central (SAC) consisted mainly of the axons of the stratum griseum centrale (SGC) and the large tectal, pyriform, and horizontal neurons.Inducible nitric oxide synthase (iNOS) was expressed in the neuropil of the SAC synaptic layer and granule cells of the stratum periventricular (SPV). Also, transforming growth factor beta (TGF‐β), SRY‐box transcription factor 9 (SOX9), and myostatin were clearly expressed in the proliferative neurons.The existence of astrocytes, proliferative neurons, and stem cells highlights the regenerative capacity of OT. [ABSTRACT FROM AUTHOR]

Abstract Nervous systems of bilaterian animals generally consist of two cell types: neurons and glial cells. Despite accumulating data about the many important functions glial cells serve in bilaterian nervous systems, the evolutionary origin of this abundant cell type remains unclear. Current hypotheses regarding glial evolution are mostly based on data from model bilaterians. Non-bilaterian animals have been largely overlooked in glial studies and have been subjected only to morphological analysis. Here, we provide a comprehensive overview of conservation of the bilateral gliogenic genetic repertoire of non-bilaterian phyla (Cnidaria, Placozoa, Ctenophora, and Porifera). We overview molecular and functional features of bilaterian glial cell types and discuss their possible evolutionary history. We then examine which glial features are present in non-bilaterians. Of these, cnidarians show the highest degree of gliogenic program conservation and may therefore be crucial to answer questions about glial evolution.

Abstract The three-dimensional organization of the genome plays a central role in the regulation of cellular functions, particularly in the human brain. This review explores the intricacies of chromatin organization, highlighting the distinct structural patterns observed between neuronal and non-neuronal brain cells. We integrate findings from recent studies to elucidate the characteristics of various levels of chromatin organization, from differential compartmentalization and topologically associating domains (TADs) to chromatin loop formation. By defining the unique chromatin landscapes of neuronal and non-neuronal brain cells, these distinct structures contribute to the regulation of gene expression specific to each cell type. In particular, we discuss potential functional implications of unique neuronal chromatin organization characteristics, such as weaker compartmentalization, neuron-specific TAD boundaries enriched with active histone marks, and an increased number of chromatin loops. Additionally, we explore the role of Polycomb group (PcG) proteins in shaping cell-type-specific chromatin patterns. This review further emphasizes the impact of variations in chromatin architecture between neuronal and non-neuronal cells on brain development and the onset of neurological disorders. It highlights the need for further research to elucidate the details of chromatin organization in the human brain in order to unravel the complexities of brain function and the genetic mechanisms underlying neurological disorders. This research will help bridge a significant gap in our comprehension of the interplay between chromatin structure and cell functions.

The traditional neuron-centric view of the central nervous system (CNS) is shifting toward recognizing the importance of communication between the neurons and the network of glial cells. This shift is leading to a more comprehensive understanding of how glial cells contribute to CNS function. Alongside this shift, recent discoveries have illuminated the significant role of the human microbiome, comprising trillions of microorganisms, mirroring the number of human cells in an individual. This paper delves into the multifaceted functions of neuroglia, or glial cells, which extend far beyond their traditional roles of supporting and protecting neurons. Neuroglia modulate synaptic activity, insulate axons, support neurogenesis and synaptic plasticity, respond to injury and inflammation, and engage in phagocytosis. Meanwhile, the microbiome, long overlooked, emerges as a crucial player in brain functionality akin to glial cells. This review aims to underscore the importance of the interaction between glial cells and resident microorganisms in shaping the development and function of the human brain, a concept that has been less studied. Through a comprehensive examination of existing literature, we discuss the mechanisms by which glial cells interface with the microbiome, offering insights into the contribution of this relationship to neural homeostasis and health. Furthermore, we discuss the implications of dysbiosis within this interaction, highlighting its potential contribution to neurological disorders and paving the way for novel therapeutic interventions targeting both glial cells and the microbiome.

Abstract Critical periods are temporally-restricted, early-life windows when sensory experience remodels synaptic connectivity to optimize environmental input. In the Drosophila juvenile brain, critical period experience drives synapse elimination, which is transiently reversible. Within olfactory sensory neuron (OSN) classes synapsing onto single projection neurons extending to brain learning/memory centers, we find glia mediate experience-dependent pruning of OSN synaptic glomeruli downstream of critical period odorant exposure. We find glial projections infiltrate brain neuropil in response to critical period experience, and use Draper (MEGF10) engulfment receptors to prune synaptic glomeruli. Downstream, we find antagonistic Basket (JNK) and Puckered (DUSP) signaling is required for the experience-dependent translocation of activated Basket into glial nuclei. Dependent on this signaling, we find critical period experience drives expression of the F-actin linking signaling scaffold Cheerio (FLNA), which is absolutely essential for the synaptic glomeruli pruning. We find Cheerio mediates experience-dependent regulation of the glial F-actin cytoskeleton for critical period remodeling. These results define a sequential pathway for experience-dependent brain synaptic glomeruli pruning in a strictly-defined critical period; input experience drives neuropil infiltration of glial projections, Draper/MEGF10 receptors activate a Basket/JNK signaling cascade for transcriptional activation, and Cheerio/FLNA induction regulates the glial actin cytoskeleton to mediate targeted synapse phagocytosis.

Abstract Ischemic stroke is a sudden and acute disease characterized by neuronal death, increment of reactive gliosis (reactive microglia and astrocytes), and a severe inflammatory process. Neuroinflammation is an early event after cerebral ischemia, with microglia playing a leading role. Reactive microglia involve functional and morphological changes that drive a wide variety of phenotypes. In this context, deciphering the molecular mechanisms underlying such reactive microglial is essential to devise strategies to protect neurons and maintain certain brain functions affected by early neuroinflammation after ischemia. Here, we studied the role of mammalian target of rapamycin (mTOR) activity in the microglial response using a murine model of cerebral ischemia in the acute phase. We also determined the therapeutic relevance of the pharmacological administration of rapamycin, a mTOR inhibitor, before and after ischemic injury. Our data show that rapamycin, administered before or after brain ischemia induction, reduced the volume of brain damage and neuronal loss by attenuating the microglial response. Therefore, our findings indicate that the pharmacological inhibition of mTORC1 in the acute phase of ischemia may provide an alternative strategy to reduce neuronal damage through attenuation of the associated neuroinflammation.

Nervous systems of bilaterian animals generally consist of two cell types: neurons and glial cells. Despite accumulating data about the many important functions glial cells serve in bilaterian nervous systems, the evolutionary origin of this abundant cell type remains unclear. Current hypotheses regarding glial evolution are mostly based on data from model bilaterians. Non-bilaterian animals have been largely overlooked in glial studies and have been subjected only to morphological analysis. Here, we provide a comprehensive overview of conservation of the bilateral gliogenic genetic repertoire of non-bilaterian phyla (Cnidaria, Placozoa, Ctenophora, and Porifera). We overview molecular and functional features of bilaterian glial cell types and discuss their possible evolutionary history. We then examine which glial features are present in non-bilaterians. Of these, cnidarians show the highest degree of gliogenic program conservation and may therefore be crucial to answer questions about glial evolution. [ABSTRACT FROM AUTHOR]

Background: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model. Methods: Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala. Results: C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression. Limitations: Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic. Conclusions: Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability. [ABSTRACT FROM AUTHOR]

Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both adlibitum feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control. [ABSTRACT FROM AUTHOR]

Clinical treatment options to combat Encephalopathy of Prematurity (EoP) are still lacking. We, and others, have proposed (intranasal) mesenchymal stem cells (MSCs) as a potent therapeutic strategy to boost white matter repair in the injured preterm brain. Using a double-hit mouse model of diffuse white matter injury, we previously showed that the efficacy of MSC treatment was time dependent, with a significant decrease in functional and histological improvements after the postponement of cell administration. In this follow-up study, we aimed to investigate the mechanisms underlying this loss of therapeutic efficacy. Additionally, we optimized the regenerative potential of MSCs by means of genetic engineering with the transient hypersecretion of beneficial factors, in order to prolong the treatment window. Though the cerebral expression of known chemoattractants was stable over time, the migration of MSCs to the injured brain was partially impaired. Moreover, using a primary oligodendrocyte (OL) culture, we showed that the rescue of injured OLs was reduced after delayed MSC coculture. Cocultures of modified MSCs, hypersecreting IGF1, LIF, IL11, or IL10, with primary microglia and OLs, revealed a superior treatment efficacy over naïve MSCs. Additionally, we showed that the delayed intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, improved myelination and the functional outcome in EoP mice. In conclusion, the impaired migration and regenerative capacity of intranasally applied MSCs likely underlie the observed loss of efficacy after delayed treatment. The intranasal administration of IGF1-, LIF-, or IL11-hypersecreting MSCs, is a promising optimization strategy to prolong the window for effective MSC treatment in preterm infants with EoP. [ABSTRACT FROM AUTHOR]

Oligodendrocyte progenitor cells (OPCs) represent a subtype of glia, giving rise to oligodendrocytes, the myelin-forming cells in the central nervous system (CNS). While OPCs are highly proliferative during development, they become relatively quiescent during adulthood, when their fate is strictly influenced by the extracellular context. In traumatic injuries and chronic neurodegenerative conditions, including those of autoimmune origin, oligodendrocytes undergo apoptosis, and demyelination starts. Adult OPCs become immediately activated; they migrate at the lesion site and proliferate to replenish the damaged area, but their efficiency is hampered by the presence of a glial scar—a barrier mainly formed by reactive astrocytes, microglia and the deposition of inhibitory extracellular matrix components. If, on the one hand, a glial scar limits the lesion spreading, it also blocks tissue regeneration. Therapeutic strategies aimed at reducing astrocyte or microglia activation and shifting them toward a neuroprotective phenotype have been proposed, whereas the role of OPCs has been largely overlooked. In this review, we have considered the glial scar from the perspective of OPCs, analysing their behaviour when lesions originate and exploring the potential therapies aimed at sustaining OPCs to efficiently differentiate and promote remyelination. [ABSTRACT FROM AUTHOR]

Since the days of Ramón y Cajal, the vast diversity of neuronal and particularly dendrite morphology has been used to catalog neurons into different classes. Dendrite morphology varies greatly and reflects the different functions performed by different types of neurons. Significant progress has been made in our understanding of how dendrites form and the molecular factors and forces that shape these often elaborately sculpted structures. Here, we review work in the nematode Caenorhabditis elegans that has shed light on the developmental mechanisms that mediate dendrite morphogenesis with a focus on studies investigating ciliated sensory neurons and the highly elaborated dendritic trees of somatosensory neurons. These studies, which combine time-lapse imaging, genetics, and biochemistry, reveal an intricate network of factors that function both intrinsically in dendrites and extrinsically from surrounding tissues. Therefore, dendrite morphogenesis is the result of multiple tissue interactions, which ultimately determine the shape of dendritic arbors. [ABSTRACT FROM AUTHOR]

Microglia are specialized immune cells unique to the central nervous system (CNS). Microglia have a highly plastic morphology that changes rapidly in response to injury or infection. Qualitative and quantitative measurements of ever-changing microglial morphology are considered a cornerstone of many microglia-centric research studies. The distinctive morphological variations seen in microglia are a useful marker of inflammation and severity of tissue damage. Although a wide array of damage-associated microglial morphologies has been documented, the exact functions of these distinct morphologies are not fully understood. In this review, we discuss how microglia morphology is not synonymous with microglia function, however, morphological outcomes can be used to make inferences about microglial function. For a comprehensive examination of the reactive status of a microglial cell, both histological and genetic approaches should be combined. However, the importance of quality immunohistochemistry-based analyses should not be overlooked as they can succinctly answer many research questions. In this review, we discuss how microglia morphology is not synonymous with microglia function, however, morphological outcomes can be used to make inferences about microglial function. Graphical Abstract [ABSTRACT FROM AUTHOR]

Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease‐modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming‐induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip‐10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease‐modifying therapeutics. [ABSTRACT FROM AUTHOR]

The traditional neuron-centric view of the central nervous system (CNS) is shifting toward recognizing the importance of communication between the neurons and the network of glial cells. This shift is leading to a more comprehensive understanding of how glial cells contribute to CNS function. Alongside this shift, recent discoveries have illuminated the significant role of the human microbiome, comprising trillions of microorganisms, mirroring the number of human cells in an individual. This paper delves into the multifaceted functions of neuroglia, or glial cells, which extend far beyond their traditional roles of supporting and protecting neurons. Neuroglia modulate synaptic activity, insulate axons, support neurogenesis and synaptic plasticity, respond to injury and inflammation, and engage in phagocytosis. Meanwhile, the microbiome, long overlooked, emerges as a crucial player in brain functionality akin to glial cells. This review aims to underscore the importance of the interaction between glial cells and resident microorganisms in shaping the development and function of the human brain, a concept that has been less studied. Through a comprehensive examination of existing literature, we discuss the mechanisms by which glial cells interface with the microbiome, offering insights into the contribution of this relationship to neural homeostasis and health. Furthermore, we discuss the implications of dysbiosis within this interaction, highlighting its potential contribution to neurological disorders and paving the way for novel therapeutic interventions targeting both glial cells and the microbiome. [ABSTRACT FROM AUTHOR]

Macrophage migration inhibitory factor (MIF) is a cytokine in the immune system, participated in both innate and adaptive immune responses. Except from immune cells, MIF is also secreted by a variety of non-immune cells, including hematopoietic cells, endothelial cells (ECs), and neurons. MIF plays a crucial role in various diseases, such as sepsis, rheumatoid arthritis, acute kidney injury, and neurodegenerative diseases. The role of MIF in the neuropathogenesis of cognitive impairment disorders is emphasized, as it recruits multiple inflammatory mediators, leading to activating microglia or astrocyte-derived neuroinflammation. Furthermore, it contributes to the cell death of neurons and ECs with the binding of apoptosis-inducing factor (AIF) through parthanatos-associated apoptosis-inducing factor nuclease (PAAN) / MIF pathway. This review comprehensively delves into the relationship between MIF and the neuropathogenesis of cognitive impairment disorders, providing a series of emerging MIF-targeted pharmaceuticals as potential treatments for cognitive impairment disorders. [Display omitted] • MIF modulates neuronal and glial function in brain. • MIF-induced neuroinflammation and cell death contributed to cognitive impairment. • MIF inhibitors are promising to prevent cognitive impairment disorders. [ABSTRACT FROM AUTHOR]