The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

Astrocytes in the retina and optic nerve head play an important role in the pathogenesis of glaucoma. Astrocytes extensively express connexin 43 (Cx43), a protein that forms gap junction (GJ) channels and transmembrane unopposed hemichannels. While it is well documented that Cx43 expression is augmented in retinal injuries, the role of astrocytic Cx43 channels in glaucomatous injury is not fully understood. Here, we used a mouse model of ocular hypertension caused by intracameral microbead injections and a more severe model, optic nerve crush (ONC) injury, and assessed changes in Cx43 expression and GJ channel function. The effect of astrocyte-specific deletion of Cx43 (Cx43KO) on retinal ganglion cell (RGC) loss and visual function was also assessed. We show that the Cx43 expression is increased in retinal astrocytes at early time points and remained elevated even after sustained elevation of intraocular pressure (IOP) (~8 weeks), which paralleled an increase in astrocytic GJ coupling. Deletion of astrocytic Cx43 markedly improved the survival of RGCs by ~93% and preserved visual function as assessed by ERG and reduced numbers of activated microglial/macrophages in the glaucomatous retina. Cx43 expression was also substantially increased after ONC injury, and the absence of Cx43 in this model increased RGC survival by ~48%. These results reveal a deleterious role for Cx43 in glaucoma progression. Intravitreal injections of Gap19, a peptide that reportedly inhibits Cx43 hemichannels but not GJ channels, markedly increased RGC survival and visual function. Further studies are required to assess whether targeting Cx43 hemichannels might be useful for glaucoma treatment.

Individual protoplasmic astrocytes have very complex and diverse spongiform shapes. The morphological diversity of astrocytes is determined by the structural and functional interactions of the astrocyte with its microenvironment. When faced with pathological conditions, astrocytes reorganize their morphology. Yet, little is known about the astrocytic response in pure tauopathies and its evolution over time. Here, we aimed to investigate the consequences of a primary neuronal tau pathology on astrocyte fine morphology at three stages of the disease using the transgenic Thy-Tau22 mouse model. We first showed that hippocampal astrocytes in Thy-Tau22 mice progressively accumulate hyperphosphorylated tau with age. We then developed a pipeline of analyses, including 3D reconstruction of hippocampal tdTomato-labeled astrocytes via a PHP.eB adeno-associated virus, confocal microscopy, Imaris software morphometric analysis, and an advanced statistical analysis. During normal aging, the complexity of astrocyte morphology peaked at adulthood, then declined. In contrast, in Thy-Tau22 mice, tauopathy was associated with a simpler initial morphology, followed by the appearance of a cluster of complex cells at the most advanced stage. Using principal component analysis and hierarchical clustering based on 10 morphological features, we were able to identify different astrocyte morphotypes whose relative proportion varies differently with age between WT and Thy-Tau22 mice. Interestingly, we revealed that a fraction of astrocytes with a complex morphology re-emerges late in tauopathy-affected animals. Our data highlight the concept of significant and reversible structural plasticity of astrocytes when faced with chronic pathological conditions.

Astrocytes are the most abundant glial cell type in the central nervous system (CNS). Astrocytes are born during the early postnatal period in the rodent brain and mature alongside neurons, demonstrating remarkable morphological structural complexity, which is attained in the second postnatal month. Throughout this period of development and across the remainder of the lifespan, astrocytes participate in CNS homeostasis, support neuronal partners, and contribute to nearly all aspects of CNS function. In the present study, we analyzed astrocyte gene expression in the cortex of wild-type male rodents throughout their lifespan (postnatal 7 days to 18 months). A pairwise timepoint comparison of differential gene expression during early development and CNS maturation (7-60 days) revealed four unique astrocyte gene clusters, each with hundreds of genes, which demonstrate unique temporal profiles. These clusters are distinctively related to cell division, cell morphology, cellular communication, and vascular structure and regulation. A similar analysis across adulthood and in the aging brain (3 to 18 months) identified similar patterns of grouped gene expression related to cell metabolism and cell structure. Additionally, our analysis identified that during the aging process astrocytes demonstrate a bias toward shorter transcripts, with loss of longer genes related to synapse development and a significant increase in shorter transcripts related to immune regulation and the response to DNA damage. Our study highlights the critical role that astrocytes play in maintaining CNS function throughout life and reveals molecular shifts that occur during development and aging in the cortex of male mice.

Astrocytes are neuromodulator cells. Their complex and dynamic morphology regulates neuronal signaling, synaptic plasticity, and neurogenesis. The impact of aging on astrocyte morphology is still under ongoing debate. Therefore, this study aimed to characterize astrocyte morphology in the hippocampus of older rats. 2-, 18-, and 20-month-old male Wistar rats were submitted to the object recognition test to assess their short- and long-term memories. CA1, CA2, CA3, and the dentate gyrus were collected for immunohistochemistry analysis and glial fibrillary acid protein (GFAP) immunostaining. Our results indicate that 20-month-old rats did not recognize or discriminate the novel object in the long-term memory test. Also, GFAP staining was greater in the oldest group for all analyzed areas. Morphometric and fractal analysis indicated shorter branch lengths and smaller sizes for astrocytes of 20-month-old rats. Overall, our results suggest that 20-month-old rats have long-term memory impairment, increased GFAP staining, and astrocyte dystrophy. These age-related alterations in astrocyte morphology are a resource for future studies exploring the role of astrocytes in age-related cognitive decline and age-related diseases.

Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF and post-mortem cortical tissue of patients at grade IV of HE. In both mice and post-mortem human tissues astrocytic primary branches demonstrated the territory occupied by astrocytes was increased, confirming astrocytic oedema. Astrocytic primary branches demonstrated swelling, while terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. In mice these morphological changes develop in parallel with decreased expression of proteins critical for astrocytic modelling and function: the water channel aquaporin 4 (AQP4), the phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1 (PFN1). Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in EEG power and by excessive glutamate in the brain microdialysates. We propose that HE evokes disease-specific remodelling of astrocytes to a "mixed", oedematic/atrophic phenotype. Concurrence of HE-specific phenotype with alterations in the expression of astrocytic proteins are a likely cause of aberrant astrocyte synaptic support resulting in severe, often fatal brain malfunction in HE.

Reactive gliosis is a hallmark of neuropathology and offers a potential target for addressing numerous neurological diseases. Here, we show that growth arrest and DNA damage inducible gamma (GADD45G), a stress sensor in astrocytes, is a nodal orchestrator of reactive gliosis and neurodegeneration. GADD45G expression in astrocytes is sufficient to incite astrogliosis, microgliosis, synapse loss, compromised animal behavior, and the aggravation of Alzheimer's disease (AD). Conversely, silencing GADD45G specifically in astrocytes preserves synapses and rescues the histological and behavioral phenotypes of AD. Mechanistically, GADD45G controls the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) and neuroimmune signaling pathways, including nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3), leading to profound molecular changes and the secretion of various factors that regulate both cell-autonomous and cell-nonautonomous reactive gliosis and glia-neuron interactions. These results uncover GADD45G signaling as a promising therapeutic target for AD and potentially for numerous other neurological disorders.

The prefrontal cortex (PFC) is an essential driver of cognitive, affective, and motivational behavior. There is clear evidence that the neuroimmune system directly influences PFC synapses, in addition to its role as the first line of defense against toxins and pathogens. In this review, we first describe the core structures that form the tetrapartite PFC synapse, focusing on the signaling microdomain created by astrocytic cradling of the synapse as well as the emerging role of the extracellular matrix in synaptic organization and plasticity. Neuroimmune signals (e.g. pro-inflammatory interleukin 1β) can impact the function of each core structure within the tetrapartite synapse, as well as promote intra-synaptic crosstalk, and we will provide an overview of recent advances in this field. Finally, evidence from post mortem human brain tissue and preclinical studies indicate that inflammation may be a key contributor to PFC dysfunction. Therefore, we conclude with a mechanistic discussion of neuroimmune-mediated maladaptive plasticity in neuropsychiatric disorders, with a focus on alcohol use disorder (AUD). Growing recognition of the neuroimmune system's role as a critical regulator of the PFC tetrapartite synapse provides strong support for targeting the neuroimmune system to develop new pharmacotherapeutics.

Dysbiosis is a characteristic of patients with Alzheimer's disease (AD). The disbalance between Gram-negative and Gram-positive bacteria causes increased production of beta-amyloid (Aβ) in the gut, which can contribute to brain accumulation of Aβ. Recovering microbiota composition with symbiotic administration of prebiotics and probiotics may be a strategy to prevent or reduce AD symptomathology. The aim of this research was to study whether chronic administration of pre- and probiotics modifies the histopathological signs of neurodegeneration in the cortex of APP/PS1 mice, a transgenic mouse model of AD. We focused on neuritic plaques deposition, neuronal degeneration and glia activation.

Transgenic (TG) mice and Wild type (WT) littermates were fed daily with a diet supplemented with prebiotics (a multi-extract of fibers and plant complexes, containing inulin/fruit-oligosaccharides) and probiotics (a 50%-50% mixture of Lactobacillus rhamnosus and Lactobacillus paracasei). The treatment started at 2 months of age and lasted for 6 months. Controls were WT and TG mice fed with a standard diet. All groups were evaluated qualitatively and quantitatively by immunofluorescence, confocal microscopy and digital imaging. Cortical sections were immunostained for neuritic plaques, neurons, astrocytes, microglia, and inflammatory proteins. Qualitative and quantitative analyses were carried out by immunofluorescence, confocal microscopy and digital imaging with ImageJ software.

Quantitative analyses in TG mice demonstrated intense Aβ load and accumulation of neurofilament heavy polypeptide (NHP) in neuritic plaques, neuronal degeneration, shrinkage of the cortex, increase of GFAP expression, and microglia and astrocytes activation. All these effects were mainly evident in cortical Layer 5. The symbiotic treatment with pre- and probiotics decreased Aβ deposition and neuritic plaques in the frontoparietal cortex. In addition, the treatment decreased the degeneration of neurons, the cortical shrinkage, increased GFAP expression, and modified microglia phenomic, decreasing significantly microglia activation. The abovementioned effects of the treatment were mostly evident in cortical Layer 5.

These data confirm that prolonged dietary regimen enriched with pre- and probiotics counteracts many of the histopathological hallmarks of AD, and poses the bases for a simple, affordable treatment that may help prevent AD.

Astrocytes, the perisynaptic glial cells of the brain, play fundamental roles in sculpting synaptic circuits and instructing their remodeling and maturation during development. Astrocytes do so through a plethora of cell adhesion and secretory signaling to neurons. This rich communication between astrocytes and neurons is critical for balancing inhibitory and excitatory synaptic connectivity. Additionally, astrocytes refine neural circuits via synaptic engulfment and elimination. Here, we will review recent findings highlighting the diversity and significance of astrocyte-to-neuron communication during developmental circuit wiring. Moreover, we will point out emerging mechanisms of how neurons instruct astrocytes' maturation and synaptic functions to spotlight the essential bidirectional communication between these two cell types in shaping synaptic circuits during neurodevelopment.

Astrocytes play a pivotal role in the inflammatory response triggered by traumatic brain injury (TBI). They are not only involved in the initial inflammatory response following injury but also significantly contribute to Astrocyte activation and inflammasome release are key processes in the pathophysiology of TBI, significantly affecting the progression of secondary injury and long-term outcomes. This comprehensive review explores the complex triggering mechanisms of astrocyte activation following TBI, the intricate pathways controlling the release of inflammasomes from activated astrocytes, and the subsequent neuroinflammatory cascade and its multifaceted roles after injury. The exploration of these processes not only deepens our understanding of the neuroinflammatory cascade but also highlights the potential of astrocytes as critical therapeutic targets for TBI interventions. We then evaluate cutting-edge research aimed at targeted therapeutic approaches to modulate pro-inflammatory astrocytes and discuss emerging pharmacological interventions and their efficacy in preclinical models. Given that there has yet to be a relevant review elucidating the specific intracellular mechanisms targeting astrocyte release of inflammatory substances, this review aims to provide a nuanced understanding of astrocyte-mediated neuroinflammation in TBI and elucidate promising avenues for therapeutic interventions that could fundamentally change TBI management and improve patient outcomes. The development of secondary brain injury and long-term neurological sequelae. By releasing a variety of cytokines and chemokines, astrocytes regulate neuroinflammation, thereby influencing the survival and function of surrounding cells. In recent years, researchers have concentrated their efforts on elucidating the signaling crosstalk between astrocytes and other cells under various conditions, while exploring potential therapeutic interventions targeting these cells. This paper highlights the specific mechanisms by which astrocytes produce inflammatory mediators during the acute phase post-TBI, including their roles in inflammatory signaling, blood-brain barrier integrity, and neuronal protection. Additionally, we discuss current preclinical and clinical intervention strategies targeting astrocytes and their potential to mitigate neurological damage and enhance recovery following TBI. Finally, we explore the feasibility of pharmacologically assessing astrocyte activity post-TBI as a biomarker for predicting acute-phase neuroinflammatory changes.

The adult mammalian brain exhibits remarkable forms of neural plasticity, enabling it to adapt and reorganize in response to internal and external stimuli. These plastic mechanisms include cytogenesis, the capacity of producing new neuronal and glial cells in restricted brain regions through processes known as neuro- and gliogenesis, respectively. Although many advances have been made in understanding adult brain plastic processes associated with cell genesis, as well as its functional and behavioral implications, most of the evidence is focused on neuronal cells. Even though astrocytes play a critical role in maintaining a neurochemical and electrophysiological homeostasis in the brain and provide a pivotal support to neuronal activity, the molecular mechanisms underlying the formation and functional integration of newly formed astroglial cells are poorly understood. However, some studies have provided key insights into the molecular mechanisms driving the generation of adult neural stem cell (NSC)-derived astrocytes, focusing on the dentate gyrus of the hippocampal cytogenic niche. Recent work has demonstrated that intrinsic and extrinsic factors can modulate astrogliogenesis. In the context of neuropathogenesis, this mechanism may be compromised in the hippocampus, contributing to functional and behavioral impairments. Here, we review the mechanisms underlying NSC-derived hippocampal astrogliogenesis, examining current perspectives on how adult-born astrocytes develop in the adult brain, their functional relevance, and the intricate regulation of the astrogliogenic process.

Obsessive-compulsive disorder (OCD) has long been conceptualized as a neuron-centric disorder of cortico-striato-thalamo-cortical (CSTC) circuit dysregulation. However, a growing body of evidence is now reframing this narrative, placing astrocytes-once relegated to passive support roles-at the center of OCD pathophysiology. Astrocytes are critical regulators of glutamate and GABA homeostasis, calcium signaling, and synaptic plasticity, all of which are disrupted in OCD. Recent high-resolution molecular and proteomic studies reveal that specific astrocyte subpopulations, including Crym-positive astrocytes, directly shape excitatory/inhibitory balance and control perseverative behaviors by modulating presynaptic inputs from the orbitofrontal cortex. Disruptions in astrocytic neurotransmitter clearance and dopamine metabolism amplify CSTC circuit hyperactivity and reinforce compulsions. This review reframes OCD as a disorder of neuro-glial dysfunctions, proposing that targeting astrocytic signaling, metabolism, and structural plasticity may unlock transformative therapeutic strategies. By integrating human and animal data, we advocate for a glial-centric model of OCD that not only enhances mechanistic understanding but also opens new frontiers for precision treatment.

Emerging evidence indicates that astrocytes modulate energy metabolism and homeostasis. However, one important but poorly understood element is the necessity of astrocytes in the control of body weight. Here, we apply viral vector-assisted brain-region selective loss of astrocytes to define physiological roles played by astrocytes in the arcuate nucleus of the hypothalamus (ARH) and to elucidate the involved mechanism. We find that astrocyte loss potently augments body weight in adult mice fed chow or high-fat diet. Mechanistically, we find that the loss of astrocytes reduces adipose tissue norepinephrine (NE) contents and chemogenetic stimulation of adipose tissue sympathetic inputs reverses the astrocyte loss-induced increase in body weight. Collectively, our findings in this study suggest a crucial physiological role of astrocytes in preventing diet-induced energy surfeit and obesity by modulating adipose tissue lipid metabolism through central sympathetic outflows to adipose tissues.

The study of the human nervous system remains challenging due to its inherent complexity and difficulty in obtaining original samples. Three-dimensional (3D) bioprinting is a rapidly evolving technology in the field of tissue engineering that has made significant contributions to several disciplines, including neuroscience. In order to more accurately reflect the intricate multicellular milieu of the in vivo environment, an increasing number of studies have commenced experimentation with the coprinting of diverse cell types. This article provides an overview of technical details and the application of 3D bioprinting with multiple cell types in the field of neuroscience, focusing on the challenges of coprinting and the research conducted based on multicellular printing. This review discusses cell interactions in coprinting systems, stem cell applications, the construction of brain-like organoids, the establishment of disease models, and the potential for integrating 3D bioprinting with other 3D culture techniques.

Synaptic dysfunction is a common feature across a broad spectrum of brain diseases, spanning from psychopathologies such as post-traumatic stress disorder (PTSD) and substance use disorders (SUD) to neurodegenerative diseases like Alzheimer's and Parkinson's disease (AD and PD). While neuroscience research aiming to understand the mechanisms underlying synaptic dysfunction has traditionally focused on the neuronal elements of the synapse, recent research increasingly acknowledges the contribution of astrocytes as a third element controlling synaptic transmission. This also sparked interest to investigate the tripartite synapse and its role in the etiology of neurological diseases. According to recent evidence, changes in the structural interaction between astrocytes and synapses not only play a pivotal role in modulating synaptic function and behavioral states, but are also implicated in the initiation and progression of various brain diseases. This review aims to integrate recent findings that provide insight into the molecular mechanisms underpinning astrocytic structural changes at the synapse. We offer a comprehensive discussion of the potential implications of compromised astrocyte-synapse interactions, and put forward that astrocytic synaptic coverage is generally reduced in numerous neurological disorders, with the extent of it being disease- and stage- specific. Finally, we propose outstanding questions on astrocyte-synapse structural plasticity that are relevant for future therapeutic strategies to tackle neurodegenerative and neuropsychiatric diseases.

This review provides a comprehensive overview of hereditary spastic paraplegias (HSPs) and summarizes the recent progress on the role of glial cells in the pathogenesis of HSPs. HSPs are a heterogeneous group of neurogenetic diseases characterized by axonal degeneration of cortical motor neurons, leading to muscle weakness and atrophy. Though the contribution of glial cells, especially astrocytes, to the progression of other motor neuron diseases like amyotrophic lateral sclerosis (ALS) is well documented, the role of glial cells and the interaction between neurons and astrocytes in HSP remained unknown until recently. Using human pluripotent stem cell-based models of HSPs, a study reported impaired lipid metabolisms and reduced size of lipid droplets in HSP astrocytes. Moreover, targeting lipid dysfunction in astrocytes rescues axonal degeneration of HSP cortical neurons, demonstrating a non-cell-autonomous mechanism in axonal deficits of HSP neurons. In addition to astrocytes, recent studies revealed dysfunctions in HSP patient pluripotent stem cell-derived microglial cells. Increased microgliosis and pro-inflammation factors were also observed in HSP patients' samples, pointing to an exciting role of innate immunity and microglia in HSP. Building upon these recent studies, further investigation of the detailed molecular mechanism and the interplay between glial cell dysfunction and neuronal degeneration in HSP by combining human stem cell models, animal models, and patient samples will open avenues for identifying new therapeutic targets and strategies for HSP.

Dependence is a hallmark of alcohol use disorder characterized by excessive alcohol intake and withdrawal symptoms. The central nucleus of the amygdala (CeA) is a key brain structure underlying the synaptic and behavioral consequences of ethanol dependence. While accumulating evidence suggests that astrocytes regulate synaptic transmission and behavior, there is a limited understanding of the role astrocytes play in ethanol dependence. The present study used a combination of viral labeling, super resolution confocal microscopy, 3D image analysis, and slice electrophysiology to determine the effects of chronic intermittent ethanol (CIE) exposure on astrocyte plasticity in the CeA. During withdrawal from CIE exposure, we observed increased GABA transmission, an upregulation in astrocytic GAT3 levels, and an increased proximity of astrocyte processes near CeA synapses. Furthermore, GAT3 levels and synaptic proximity were positively associated with voluntary ethanol drinking in dependent rats. Slice electrophysiology confirmed that the upregulation in astrocytic GAT3 levels was functional, as CIE exposure unmasked a GAT3-sensitive tonic GABA current in the CeA. A causal role for astrocytic GAT3 in ethanol dependence was assessed using viral-mediated GAT3 overexpression and knockdown approaches. However, GAT3 knockdown or overexpression had no effect on somatic withdrawal symptoms, dependence-escalated ethanol intake, aversion-resistant drinking, or post-dependent ethanol drinking in male or female rats. Moreover, intra-CeA pharmacological inhibition of GAT3 did not alter dependent ethanol drinking. Together, these findings indicate that ethanol dependence induces GABAergic dysregulation and astrocyte plasticity in the CeA. However, these changes in astrocytic GAT3 do not appear to be necessary for the drinking related phenotypes associated with dependence.

Neuromodulation encompasses different processes that regulate neuronal and network function. Classical neuromodulators originating from long-range nuclei, such as acetylcholine, norepinephrine, or dopamine, act with a slower time course and wider spatial range than fast synaptic transmission and action potential firing. Accumulating evidence in vivo indicates that astrocytes, which are known to actively participate in synaptic function at tripartite synapses, are also involved in neuromodulatory processes. The present article reviews recent findings obtained in vivo indicating that astrocytes express receptors for neuromodulators that elevate their internal calcium and stimulate the release of gliotransmitters, which regulate synaptic and network function, and hence mediate, at least partially, the effects of neuromodulators. In addition, we propose that astrocytes act in local support of neuromodulators by spatially and temporally integrating neuronal and neuromodulatory signals to regulate neural network function. The presence of astrocyte-neuron hysteresis loops suggests astrocyte-neuron interaction at tripartite synapses scales up to astrocyte-neuronal networks that modulate neural network function. We finally propose that astrocytes sense the environmental conditions, including neuromodulators and network function states, and provide homeostatic control that maximizes the dynamic range of neural network activity. In summary, we propose that astrocytes are critical in mediating the effects of neuromodulators, and they also act as neuromodulators to provide neural network homeostasis thus optimizing information processing in the brain. Hence, astrocytes sense ongoing neuronal activity along with neuromodulators and, acting as neuromodulators, inform the neurons about the state of the internal system and the external world.

Spinal cord injury (SCI) can impair motor, sensory, and autonomic function. The formation of the glial scar comprises protective as well as inhibitory neurite outgrowth properties operated by the deposition of chondroitin sulfate proteoglycans (CSPG). Chondroitinase ABC (ChABC) can degrade CSPG and foster neuroaxonal plasticity as a therapeutic approach to restore locomotor function after SCI.

To systematically review experimental ChABC treatments after SCI and assess their efficacy for locomotor function a comprehensive literature search was conducted following pre-registered Prospero Study protocol, selecting animal studies evaluating neurobehavioral outcomes after traumatic SCI followed by the calculation of normalized effect sizes applying meta-analysis and meta-regression methodology. Additional analyses were performed to investigate the impact of animal type, strain, sex, sample size, injury models, level of injury, and treatment duration.

Within the overall analysis of 1066 animals, a considerable amount of heterogeneity was observed. A subgroup analysis comprising experiments applying the same neurobehavioral measurement (blood-brain barrier/Basso-Mouse-Scale [BMS]-subgroup) demonstrated a 15.9% (95% CI = 11.3%-20.6%) improvement in locomotor outcomes. Different experimental characteristics influenced neurological recovery, including sex, level of injury, used anesthetic, reported dosage of ChABC treatment, the timepoint of assessment and perioperative temperature control. Sensitivity analysis applying Trim and Fill identified 19 hypothetical missing experiments suggestive of reporting bias.

Reporting bias in experimental SCI research is prevalent and not limited to a specific intervention. ChABC treatment can exert beneficial effects on locomotor recovery after SCI.

General anesthetics (GAs) are conventionally thought to induce loss of consciousness (LOC) by acting on pre- and post-synaptic targets. However, the mechanism underlying the involvement of astrocytes in LOC remains unclear. Here we report that inhaled GAs cause reversible impairments in the fine processes of astrocytes within the somatosensory cortex, mediated by regulating the phosphorylation level of Ezrin, a protein critical for the fine morphology of astrocytes. Genetically deleting Ezrin or disrupting its phosphorylation was sufficient to decrease astrocyte-synapse interaction and enhance sensitivity to sevoflurane (Sevo) in vivo. Moreover, we show that disrupting astrocytic Ezrin phosphorylation boosted the inhibitory effect of Sevo on pyramidal neurons by enhancing tonic GABA and lowering excitability under anesthesia. Our work reveals previously unappreciated phosphorylation-dependent morphological dynamics, which enable astrocytes to regulate neuronal activity during the transition between two brain consciousness states.

Neuropathic pain is a prevalent and debilitating condition experienced by the majority of individuals with spinal cord injury (SCI). The complex pathophysiology of neuropathic pain, involving continuous activation of microglia and astrocytes, reactive gliosis, and altered neuronal plasticity, poses significant challenges for effective treatment. This review focuses on the pivotal roles of microglia and astrocytes, the two major glial cell types in the central nervous system, in the development and maintenance of neuropathic pain after SCI. We highlight the extensive bidirectional interactions between these cells, mediated by the release of inflammatory mediators, neurotransmitters, and neurotrophic factors, which contribute to the amplification of pain signaling. Understanding the microglia-astrocyte crosstalk and its impact on neuronal function is crucial for developing novel therapeutic strategies targeting neuropathic pain. In addition, this review discusses the fundamental biology, post-injury pain roles, and therapeutic prospects of microglia and astrocytes in neuropathic pain after SCI and elucidates the specific signaling pathways involved. We also speculated that the extracellular matrix (ECM) can affect the glial cells as well. Furthermore, we also mentioned potential targeted therapies, challenges, and progress in clinical trials, as well as new biomarkers and therapeutic targets. Finally, other relevant cell interactions in neuropathic pain and the role of glial cells in other neuropathic pain conditions have been discussed. This review serves as a comprehensive resource for further investigations into the microglia-astrocyte interaction and the detailed mechanisms of neuropathic pain after SCI, with the aim of improving therapeutic efficacy.

This paper examines different computational models for Calcium wave propagation in astrocytes. Through a comparative analysis of models by Goldbeter, De Young-Keizer, Atri, Li-Rinzel, and De Pittà and of experimental data, the study highlights the model contributions for the understanding of Calcium dynamics. Tracing the evolution from simple to complex models, this work emphasizes the importance of integrating experimental data in order to further refine these models. The results allow to improve our understanding of the physiological functions of astrocytes, suggesting the importance of more accurate astrocyte models.

Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein zinc transporter 3 (ZnT3). Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses. We identify small-molecule compounds that antagonize the function of ZIP12 in heterologous expression systems, and we use one of these compounds, ZIP12 modulator 8, to increase the concentration of ZnT3-dependent zinc at synapses in the brain of male and female mice to inhibit the activity of neuronal AMPA and NMDA glutamate receptors. These results identify a cellular mechanism and provide a pharmacological toolbox to target the molecular machinery that supports the actions of synaptic zinc in the brain.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

Stressful events are associated with impaired glutamate signaling and neuroimmune adaptations that may increase the vulnerability of individuals to cocaine addiction. We previously demonstrated that chronic stress induced reactive microglia and increased TNF-α expression in the nucleus accumbens core (NAcore), both alterations strongly linked with impaired glutamate homeostasis and the facilitation of cocaine self-administration. The nuclear factor kappa-B (NF-κB) is a critical regulator of many immune- and addiction-related genes, such as the gene coding for glutamate transporter (GLT-1), and it is considered a master regulator of inflammation, reported to be a key driver of microglia activation in psychiatric diseases. However, no studies have examined the role of NF-κB signaling within the NAcore in the neuroimmune and glutamate mechanism, underpinning stress-induced vulnerability to cocaine self-administration. Here we investigate whether viral dominant negative inhibition of I kappa B kinase (IKKdn), a signaling molecule responsible for NF-κB activation, would prevent stress-induced facilitation to cocaine self-administration and associated changes in accumbal GLT-1 and TNF-α expression. We also explore N-myc proto-oncogene protein (N-myc) levels as a link between NF-κB and stress-induced GLT-1 downregulation. For seven days (days 1-7), adult male rats were restrained for 2 h/day. Animals were administered an intra-NAcore with IKKdn or empty lentiviruses on day 14 after the first restraint stress session. Marked activation of NF-κB was detected in the NAcore of stressed subjects, along with increased NF-κB expression in astrocytes. Consistently, viral NF-κB inhibition prevented stress-induced facilitation of cocaine self-administration. Moreover, NF-κB blockade results in the restoration of stress-induced reduction in GLT-1 levels and was effective in suppressing stress-induced TNF-α within the NAcore. These findings suggest that accumbal NF-κB signaling exerts a central control over stress-altered downstream neuroimmune and glutamate function underlying vulnerability to cocaine use disorders.

Memory engrams are formed through experience-dependent plasticity of neural circuits, but their detailed architectures remain unresolved. Using three-dimensional electron microscopy, we performed nanoscale reconstructions of the hippocampal CA3-CA1 pathway after chemogenetic labeling of cellular ensembles recruited during associative learning. Neurons with a remote history of activity coinciding with memory acquisition showed no strong preference for wiring with each other. Instead, their connectomes expanded through multisynaptic boutons independently of the coactivation state of postsynaptic partners. The rewiring of ensembles representing an initial engram was accompanied by input-specific, spatially restricted upscaling of individual synapses, as well as remodeling of mitochondria, smooth endoplasmic reticulum, and interactions with astrocytes. Our findings elucidate the physical hallmarks of long-term memory and offer a structural basis for the cellular flexibility of information coding.

Use of brain-computer interfaces (BCIs) is rapidly becoming a transformative approach for diagnosing and treating various brain disorders. By facilitating direct communication between the brain and external devices, BCIs have the potential to revolutionize neural activity monitoring, targeted neuromodulation strategies, and the restoration of brain functions. However, BCI technology faces significant challenges in achieving long-term, stable, high-quality recordings and accurately modulating neural activity. Traditional implantable electrodes, primarily made from rigid materials like metal, silicon, and carbon, provide excellent conductivity but encounter serious issues such as foreign body rejection, neural signal attenuation, and micromotion with brain tissue. To address these limitations, hydrogels are emerging as promising candidates for BCIs, given their mechanical and chemical similarities to brain tissues. These hydrogels are particularly suitable for implantable neural electrodes due to their three-dimensional water-rich structures, soft elastomeric properties, biocompatibility, and enhanced electrochemical characteristics. These exceptional features make them ideal for signal recording, neural modulation, and effective therapies for neurological conditions. This review highlights the current advancements in implantable hydrogel electrodes, focusing on their unique properties for neural signal recording and neuromodulation technologies, with the ultimate aim of treating brain disorders. A comprehensive overview is provided to encourage future progress in this field. Implantable hydrogel electrodes for BCIs have enormous potential to influence the broader scientific landscape and drive groundbreaking innovations across various sectors.

Accumulation of astrocytes around β-amyloid (Aβ) plaques is one of the earliest neuropathological changes in Alzheimer's disease (AD), but the underlying mechanisms and significance remain unclear. Cell adhesion molecule protocadherin-γC5 (Pcdh-γC5) has been reported to implicate in AD. Here, we find elevated expression levels of Pcdh-γC5 in the brain of 5×FAD mice and Aβ-treated astrocytes and further reveal that Pcdh-γC5 deficiency leads to exacerbated Aβ deposition in 5×FAD mice. Deletion of Pcdh-γC5 impairs astrocyte migration, astrocytic response to Aβ signaling, and Aβ phagocytosis in both cultured astrocytes in vitro and 5×FAD mice in vivo. Both male and female mice were used in this study. Our findings support a model in which increased expression level of Pcdh-γC5 promotes astrocyte migration in response to Aβ signaling and engulfment and phagocytosis of neurotoxic Aβ plaques, therefore exerting a critical neuroprotective function in AD.

Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive memory loss and cognitive decline. Recent evidence indicates that inflammation plays a central role in AD pathogenesis, with elevated inflammatory markers and risk genes linked to innate immune functions. Glial cell dysfunction, particularly in astrocytes and microglia, is crucial to the neuroinflammatory process, contributing to oxidative stress, synaptic dysfunction, neuronal death, and impaired neurogenesis. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analogue, on microglial morphology, inflammation, and oxidative stress parameters in a sporadic Alzheimer-like disease model induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days significantly reduced inflammation in the hippocampus and provided protection against oxidative damage in the entorhinal cortex by activating the Nrf-2 pathway and enhancing the expression of antioxidant enzymes such as SOD1 and CAT. These findings suggest that BFT exerts neuroprotective effects in AD, particularly impacting glial cell function and redox homeostasis.

Lipid droplets serve as primary storage organelles for neutral lipids in neurons, glial cells, and other cells in the nervous system. Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum. Previously, lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis; however, recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system. In addition to their role in regulating cell metabolism, lipid droplets play a protective role in various cellular stress responses. Furthermore, lipid droplets exhibit specific functions in neurons and glial cells. Dysregulation of lipid droplet formation leads to cellular dysfunction, metabolic abnormalities, and nervous system diseases. This review aims to provide an overview of the role of lipid droplets in the nervous system, covering topics such as biogenesis, cellular specificity, and functions. Additionally, it will explore the association between lipid droplets and neurodegenerative disorders. Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

A long-lasting GABA-dependent increase in the excitability of afferent fibres, and thus modulation of the sensory input to the spinal cord, may be evoked by epidural polarization. However, the direct effects of fibre polarization are short-lasting and the sustained increase in their excitability appears to be secondary to the release of GABA from nearby astrocytes. We have now investigated whether the modulation of spinal sensory input by stimulation of a peripheral nerve, previously attributed to synaptically evoked intraspinal field potentials, is evoked in a similar way. However, as neither its dependence on GABA nor its relays have been investigated, we addressed the question of whether the increase in the excitability of epidurally stimulated afferent fibres following a peripheral nerve stimulation does or does not depend on GABA and whether it might be mediated by astrocytes. The effects of conditioning stimulation of the tibial nerve were evaluated from changes in the excitability of both Group I and II muscle afferents, estimated from action potentials recorded in peripheral nerves and in field potentials recorded in the dorsal horn respectively in acute experiments on deeply anaesthetized rats. The excitability of the afferents was increased by stimulation of Group II and/or cutaneous but not Group I muscle afferents. The effects were significantly weakened by blocking GABA channels by gabazine and by astrocyte toxin L-alpha-aminoadipic acid (L-AAA), indicating that the excitability of both Group I and II afferent fibres may be modulated by GABAergic astrocytes, the new role played by astrocytes.

Astrocytes play important roles in the central nervous system (CNS) during health and disease. Prior studies have shown that gut commensal-derived indole derivatives as well as secondary bile acids modulate astrocyte function during the late stage of EAE (recovery phase). Here we showed that administering vancomycin to mice starting during the early stage of EAE improved disease recovery, an effect that is mediated by the gut microbiota. We observed that 6 taxa within the Clostridia vadin BB60 group were enriched in vancomycin-treated mice compared to untreated EAE mice. Vancomycin-treated EAE mice also had elevated serum levels of the anti-inflammatory tryptophan-derived metabolite, indole-3-lactic acid and decreased levels of deoxycholic acid, a pro-inflammatory secondary bile acid. RNA sequencing revealed altered expression of several genes belonging to the mammalian target of rapamycin (mTOR) pathway in astrocytes obtained during the late stage of EAE from vancomycin-treated EAE mice. Furthermore, we observed a link between serum levels of indole derivatives and bile acids and expression of several genes belonging to the mTOR pathway. Interestingly, the mTOR signaling cascades have been implicated in several key biological processes including innate (e.g., astrocyte) immune responses as well as neuronal toxicity/degeneration. In addition, rapamycin, a specific inhibitor of mTOR, has been shown to inhibit the induction and progression of established EAE. Collectively, our findings suggest that the neuroprotective effect of vancomycin is at least partially mediated by indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes.

Yin Yang 1 is a ubiquitously expressed transcription factor that has been extensively studied given its particular dual transcriptional regulation. Yin Yang 1 is involved in various cellular processes like cell cycle progression, cell differentiation, DNA repair, cell survival and apoptosis among others. Its malfunction or alteration leads to disease and even to malignant transformation. This transcription factor is essential for the proper central nervous system development and function. The activity of Yin Yang 1 depends on its interacting partners, promoter environment and chromatin structure, however, its mechanistic activity is not completely understood. In this review, we briefly discuss the Yin Yang 1 structure, post-translational modifications, interactions, mechanistic functions and its participation in neurodevelopment. We also discuss its expression and critical involvement in the physiology and physiopathology of glial cells, summarizing the contribution of Yin Yang 1 on different aspects of cellular function.

Astrocytes are the most prevalent glial cells of the brain and mediate vital roles in the development and function of the nervous system. Astrocytes, along with microglia, also play key roles in initiating inflammatory immune responses following brain injury, stress, or disease-related triggers. While these glial immune responses help contain and resolve cellular damage to the brain, dysregulation of astrocyte activity can in some cases amplify inflammation and worsen impact on neural tissue. As nonexcitable cells, astrocytes excitability is regulated primarily by Ca2+ signals that control key functions such as gene expression, release of inflammatory mediators, and cell metabolism. In this review, we examine the molecular and functional architecture of Ca2+ signaling networks in astrocytes and their impact on astrocyte effector functions involved in inflammation and immunity.

Astrocytes, which actively participate in cognitive processes, have a complex spongiform morphology, highlighted by extensive ramified fine processes that closely enwrap the pre- and post-synaptic compartments, forming tripartite synapses. However, the role of astrocyte morphology in cognitive processes remains incompletely understood and even controversial. The actin-binding protein Ezrin is highly expressed in astrocytes and is a key structural determinant of astrocyte morphology. Here, we found that Ezrin expression and astrocyte fine process volume in the hippocampus of male mice increased after learning but decreased after lipopolysaccharide injection and in a mouse model of postoperative cognitive dysfunction, both of which involved models with impaired cognitive function. Additionally, astrocytic Ezrin knock-out led to significantly decreased astrocytic fine process volumes, decreased astrocyte-neuron proximity, and induced anxiety-like behaviors and cognitive dysfunction. Astrocytic Ezrin deficiency in the hippocampus was achieved by using a microRNA silencing technique delivered by adeno-associated viruses. Down-regulation of Ezrin in hippocampal astrocytes led to disrupted astrocyte-synapse interactions and impaired synaptic functions, including synaptic transmission and synaptic plasticity, which could be rescued by exogenous administration of D-serine. Remarkably, decreased Ezrin expression and reduced astrocyte fine processes volumes were also observed in aged mice with decreased cognitive function. Moreover, overexpression of astrocytic Ezrin increased astrocyte fine process volumes and improved cognitive function in aged mice. Overall, our results indicate Ezrin-mediated astrocyte fine processes integrity shapes astrocyte-synapse signaling contributing to cognitive function.

Botulinum neurotoxin type A (BoNT/A) has expanded its therapeutic uses beyond neuromuscular disorders to include treatments for various pain syndromes and neurological conditions. Originally recognized for blocking acetylcholine release at neuromuscular junctions, BoNT/A's effects extend to both peripheral and central nervous systems. Its ability to undergo retrograde transport allows BoNT/A to modulate synaptic transmission and reduce pain centrally, influencing neurotransmitter systems beyond muscle control. BoNT/A also interacts with glial cells, such as Schwann cells, satellite glial cells, astrocytes, microglia, and oligodendrocytes. Schwann cells, key to peripheral nerve regeneration, are directly influenced by BoNT/A, which promotes their proliferation and enhances remyelination. Satellite glial cells, involved in sensory neuron regulation, show reduced glutamate release in response to BoNT/A, aiding in pain relief. In the CNS, BoNT/A modulates astrocyte activity, reducing excitotoxicity and inflammation, which is relevant in conditions like epilepsy. Microglia, the CNS's immune cells, shift from a pro-inflammatory to a neuroprotective state when treated with BoNT/A, enhancing tissue repair. Additionally, BoNT/A promotes oligodendrocyte survival and remyelination, especially after spinal cord injury. Overall, BoNT/A's ability to target both neurons and glial cells presents a multifaceted therapeutic strategy for neurological disorders, pain management, and CNS repair. Further research is necessary to fully elucidate its mechanisms and optimize its clinical application.