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Chronic pain is a critical clinical problem with an increasing prevalence. However, there are limited effective prevention measures and treatments for chronic pain. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in both physiological and pathological conditions. Over the past few decades, a growing body of evidence indicates that astrocytes are involved in the regulation of chronic pain. Recently, reactive astrocytes were further classified into A1 astrocytes and A2 astrocytes according to their functions. After nerve injury, A1 astrocytes can secrete neurotoxins that induce rapid death of neurons and oligodendrocytes, whereas A2 astrocytes promote neuronal survival and tissue repair. These findings can well explain the dual effects of reactive astrocytes in central nervous injury and diseases. In this review, we will summarise the (1) changes in the morphology and function of astrocytes after noxious stimulation and nerve injury, (2) molecular regulators and signalling mechanisms involved in the activation of astrocytes and chronic pain, (3) the role of spinal and cortical astrocyte activation in chronic pain, and (4) the roles of different subtypes of reactive astrocytes (A1 and A2 phenotypes) in nerve injury that is associated with chronic pain. This review provides updated information on the role of astrocytes in the regulation of chronic pain. In particular, we discuss recent findings about A1 and A2 subtypes of reactive astrocytes and make several suggestions for potential therapeutic targets for chronic pain.

Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term “astrosenescence” to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age‐related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age‐associated neurodegenerative disease.

The idea of central nervous system as one-man band favoring neurons is long gone. Now we all are aware that neurons and neuroglia are team players and constant communication between those various cell types is essential to maintain functional efficiency and a quick response to danger. Here, we summarize and discuss known and new markers of astroglial multiple functions, their natural heterogeneity, cellular interactions, aging and disease-induced dysfunctions. This review is focused on newly reported facts regarding astrocytes, which are beyond the old stereotypes. We present an up-to-date list of marker proteins used to identify a broad spectrum of astroglial phenotypes related to the various physiological and pathological nervous system conditions. The aim of this review is to help choose markers that are well-tailored for specific needs of further experimental studies, precisely recognizing differential glial phenotypes, or for diagnostic purposes. We hope it will help to categorize the functional and structural diversity of the astroglial population and ease a clear readout of future experimental results.

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1 – 3 . Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology. A regional atlas of the ageing human brain—spanning six distinct anatomical regions from individuals with and without Alzheimer’s dementia—provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology

In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled neurodegeneration in glaucoma, the world’s leading cause of irreversible blindness, and measured how metabolites mobilize through astrocyte gap junctions composed of connexin 43 (Cx43). We elevated intraocular pressure in one eye and determined how astrocyte-derived metabolites in the contralateral optic projection responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances even 10 mm in length, donating resources from the unstressed to the stressed projection in response to intraocular pressure elevation. While resource donation improves axon function and visual acuity in the directly stressed region, it renders the donating tissue susceptible to bioenergetic, structural, and physiological degradation. Intriguingly, when both projections are stressed in a WT animal, axon function and visual acuity equilibrate between the two projections even when each projection is stressed for a different length of time. This equilibration does not occur when Cx43 is not present. Thus, Cx43-mediated astrocyte metabolic networks serve as an endogenous mechanism used to mitigate bioenergetic stress and distribute the impact of neurodegenerative disease processes. Redistribution ultimately renders the donating optic nerve vulnerable to further metabolic stress, which could explain why local neurodegeneration does not remain confined, but eventually impacts healthy regions of the brain more broadly.

Summary Astrocytes are the most abundant glial cells in the central nervous system (CNS) and participate in synaptic, circuit, and behavioral functions. The well‐developed protoplasmic astrocytes contain numerous processes forming well‐delineated bushy territories that overlap by as little as 5% at their boundaries. This highly complex morphology, with up to approximately 80% of the cell's membrane constituted by fine processes with dimensions on the tens of nanometer scale and high surface area to volume ratios, comes in contact with synapses, blood vessels, and other glial cells. Recent progress is challenging the conventional view that astrocytes are morphologically homogeneous throughout the brain; instead, they display circuit‐ and region‐specific morphological diversity that may contribute to the heterogeneous astrocyte‐neuron spatiotemporal interplay in different brain areas. Further, the fine structure of astrocytes is found to be highly plastic and activity‐dependent. We are beginning to understand how astrocyte structural plasticity contributes to brain functions. The change/loss of astrocyte morphology, traditionally known as a hallmark for reactive astrogliosis, is a common pathological feature in many neurological disorders. However, recent data suggest the fine structural deficits preceding reactive astrogliosis may drive disease progression. This review summarizes recent advances in astrocyte morphological diversity, plasticity, and disease‐related deficits.

Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange. Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19 + B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.

Astroglia are neural cells, heterogeneous in form and function, which act as supportive elements of the central nervous system; astrocytes contribute to all aspects of neural functions in health and disease. Through their highly ramified processes, astrocytes form close physical contacts with synapses and blood vessels, and are integrated into functional syncytia by gap junctions. Astrocytes interact among themselves and with other cells types (e.g., neurons, microglia, blood vessel cells) by an elaborate repertoire of chemical messengers and receptors; astrocytes also influence neural plasticity and synaptic transmission through maintaining homeostasis of neurotransmitters, K + buffering, synaptic isolation and control over synaptogenesis and synaptic elimination. Satellite glial cells (SGCs) are the most abundant glial cells in sensory ganglia, and are believed to play major roles in sensory functions, but so far research into SGCs attracted relatively little attention. In this review we compare SGCs to astrocytes with the purpose of using the vast knowledge on astrocytes to explore new aspects of SGCs. We survey the main properties of these two cells types and highlight similarities and differences between them. We conclude that despite the much greater diversity in morphology and signaling mechanisms of astrocytes, there are some parallels between them and SGCs. Both types serve as boundary cells, separating different compartments in the nervous system, but much more needs to be learned on this aspect of SGCs. Astrocytes and SGCs employ chemical messengers and calcium waves for intercellular signaling, but their significance is still poorly understood for both cell types. Both types undergo major changes under pathological conditions, which have a protective function, but an also contribute to disease, and chronic pain in particular. The knowledge obtained on astrocytes is likely to benefit future research on SGCs.

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are heterogenous, responsive to their environments, and critical regulators of brain microenvironments and neuronal function. With increasing age, astrocytes adopt different immune-related and senescence-associated states, which relate to organelle dysfunction and loss of homeostasis maintenance, both cell autonomously and non-cell autonomously. These perturbed states are increasingly associated with age-related dysfunction and the onset of neurodegeneration, suggesting that astrocyte aging is a compelling target for future manipulation in the prevention of disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.