Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders. In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.

JOURNAL/nrgr/04.03/01300535-202511000-00032/figure1/v/2024-12-20T164640Z/r/image-tiff Glial cells play crucial roles in regulating physiological and pathological functions, including sensation, the response to infection and acute injury, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system, and satellite glial cells and Schwann cells in the peripheral nervous system. Despite the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models, few studies have investigated the transcriptomic profiles of glial cells in the human spinal cord. Here, we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these findings with those from mice. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were each divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into five, four, and five distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cell types between humans and mice. Additionally, we detected sex differences in gene expression in human spinal cord glial cells. Specifically, in all astrocyte subtypes, the levels of NEAT1 and CHI3L1 were higher in males than in females, whereas the levels of CST3 were lower in males than in females. In all microglial subtypes, all differentially expressed genes were located on the sex chromosomes. In addition to sex-specific gene differences, the levels of MT-ND4 , MT2A , MT-ATP6 , MT-CO3 , MT-ND2 , MT-ND3 , and MT-CO2 in all spinal cord oligodendrocyte subtypes were higher in females than in males. Collectively, the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for exploring the cellular basis of spinal cord-related illnesses, including chronic pain, amyotrophic lateral sclerosis, and multiple sclerosis.

Vision decline in the elderly, often due to retinal aging, predisposes individuals to pathologies like age-related macular degeneration. Currently, there are few effective oral treatments for this condition. Our study introduces an oral agent, 8-aminoguanine (8-AG), which targets age-related retinal degeneration using an aged Fischer 344 rat model. When administered in drinking water at a low dose for 8 weeks starting at 22 months of age, 8-AG significantly preserves retinal structure and function, as evidenced by increased retinal thickness, enhanced photoreceptor integrity, and improved electroretinogram responses. 8-AG reduces apoptosis, oxidative damage, and microglial/macrophage activation in aging retinae. 8-AG also mitigates retinal inflammation at transcriptional and cytokine levels. Extending treatment to 17 weeks further amplifies these protective effects. Given its efficacy in various disease models, 8-AG shows great promise as an anti-aging compound with the potential to mitigate common hallmarks of aging.

Decellularized extracellular matrix derived from specific organs represents a promising platform for organoid development, offering distinct advantages in tissue engineering. This matrix maintains the complex three-dimensional network of biological macromolecules secreted by tissue-specific cells, including collagen, glycoproteins, and proteoglycans. This extracellular matrix orchestrates cellular behaviors, such as proliferation, migration, and differentiation, while maintaining optimal tissue homeostasis. The organ-specific composition of decellularized extracellular matrix preserves native biological cues, including growth factors and cytokines, as well as mechanical properties, facilitating natural cell-matrix interactions and promoting appropriate stem cell development. These characteristics make organ-derived decellularized extracellular matrix an ideal scaffold for organoid construction. The implementation of decellularized extracellular matrix enhances the physiological relevance of organoid models, which is particularly valuable in drug development, personalized medicine, and the study of complex organ microenvironments. This advancement significantly improves the translational potential of organoid technology for organ transplantation while providing robust research tools. Consequently, decellularized extracellular matrix-based organoid models offer superior platforms for preclinical therapeutic evaluation. This review examines recent progress in decellularized extracellular matrix-based organoid development, beginning with current application strategies and proceeding to an analysis of existing decellularized extracellular matrix-derived organoid models.

Early life stress (ELS), a prenatal/early postnatal period of severe trauma, social deprivation, or neglect, among other adversities, constitutes a risk factor for developing psychopathologies and different health complications in adulthood. Maternal separation with early weaning (MSEW) induces long-term consequences in mouse retinal function and structure. We analyzed microglia involvement in adult retina ELS-induced sequelae. C57Bl/6 J mice were separated from the dams at postnatal days (PND) 4-6, 7-9, 10-12, and 13-16, for 2 h, 3 h, 4 h, and 6 h, respectively, and were weaned at PND 17. Control pups were left undisturbed and weaned at PND 21. At PND 45, MSEW induced microgliosis and decreased retinal ganglion cell (RGC) function, followed by RGC loss at PND 60. Microglial phenotypic alterations correlated with a pro-inflammatory profile (i.e., increase in the nuclear levels of nuclear factor kappa B -subunit p65, and C3-, nitric oxide synthase-2, and interleukin-1β-immunoreactivity in Iba-1 ( +) cells). Depleting microglia between PND 35 and 60 did not affect the retina from naïve mice. However, in early stressed mice, it preserved RGC function and number, visually mediated behavior, and contrast sensitivity. Therefore, microglial reactivity could be one of the key factors linking progressive alterations provoked by ELS in adult mice retinal function and structure.

The inflammatory hypothesis is one of the more widely accepted pathogenesis of depression. Glia plays an important immunomodulatory role in neuroinflammation, mediating interactions between the immune system and the central nervous system (CNS). Glial cell-driven neuroinflammation is not only an important pathological change in depression, but also a potential therapeutic target. This review discusses the association between depression and glial cell-induced neuroinflammation and elucidates the role of glial cell crosstalk in neuroinflammation. Firstly, we focus on the role of glial cells in neuroinflammation in depression and glial cell interactions; secondly, we categorize changes in different glial cells in animal models of depression and depressed patients, focusing on how glial cells mediate inflammatory responses and exacerbate depressive symptoms; Thirdly, we review how conventional and novel antidepressants affect the phenotype and function of glial cells, thereby exerting anti-inflammatory activity; finally, we discuss the role of the gut-brain axis in glial cell function and depression, and objectively analyze the problems that remain in current antidepressant therapy. This review aims to provide an objective analysis of how glial cell cross-talk may mediate neuroinflammation and thereby influence pathologic progression of depression. It is concluded that a novel therapeutic strategy may be to ameliorate glial cell-mediated inflammatory responses.

Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.

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.

Microglia and astrocytes are central to the pathogenesis and progression of Alzheimer's Disease (AD), working both independently and collaboratively to regulate key pathological processes such as β-amyloid protein (Aβ) deposition, tau aggregation, neuroinflammation, and synapse loss. These glial cells interact through complex molecular pathways, including IL-3/IL-3Ra and C3/C3aR, which influence disease progression and cognitive decline. Emerging research suggests that modulating these pathways could offer therapeutic benefits. For instance, recombinant IL-3 administration in mice reduced Aβ plaques and improved cognitive functions, while C3aR inhibition alleviated Aβ and tau pathologies, restored synaptic function, and corrected immune dysregulation. However, the effects of these interactions are context-dependent. Acute C3/C3aR activation enhances microglial Aβ clearance, whereas chronic activation impairs it, highlighting the dual roles of glial signaling in AD. Furthermore, C3/C3aR signaling not only impacts Aβ clearance but also modulates tau pathology and synaptic integrity. Given AD's multifactorial nature, understanding the specific pathological environment is crucial when investigating glial cell contributions. The interplay between microglia and astrocytes can be both neuroprotective and neurotoxic, depending on the disease stage and brain region. This complexity underscores the need for targeted therapies that modulate glial cell activity in a context-specific manner. By elucidating the molecular mechanisms underlying microglia-astrocyte interactions, this research advances our understanding of AD and paves the way for novel therapeutic strategies aimed at mitigating neurodegeneration and cognitive decline in AD and related disorders.

Neuronal activity is shown to potentiate glioma initiation, progression, and/or metastasis. A key mechanism in neural regulation of brain cancer involves the activity-dependent cleavage and release of the synaptic adhesion molecule neuroligin-3 (NLGN3). Here, this report describes the preparation of optogenetics-like liposome Lip-CuRA, which is used to regulate the content of NLGN3 in neurons and mediate phototherapy in cancer cells. Lip-CuRA contains upconversion nanoparticles encapsulating CuS (CuS@PUCNPs), a visible light-activated neurotransmitter prodrug RuBi-GABA, and a disintegrin and metalloproteinase (ADAM10) inhibitors GI254023X. Upon 980 nm laser irradiation, the photothermal conversion of CuS not only induces tumor cell apoptosis, but also destroys liposome structure, releasing Rubi-GABA and GI254023X. The UCNPs convert the 980 nm laser into 540 nm, activating RuBi-GABA into GABA. GABA selectively opens Cl⁻ channels in nerve cells, reducing the expression of NLGN3 and the degree of axonal connections. GI254023X inhibits the activity of the ADAM10 enzyme on the nerve surface, reducing the release of NLGN3, thereby blocking the transmission of proliferation and stemness signals. In the GL261-luc orthotopic glioma model, C6-luc orthotopic glioma model, and glioma patient-derived xenograft (PDX) model, Lip-CuRA effectively inhibits tumor recurrence, reduces glioma stemness, and extends survival through a synergistic photothermal and NLGN3-regulating therapy.

Monocular deprivation obstructs the development of visual neural circuits and can impair vision for a lifetime. Effective treatment of this visual disorder, amblyopia, with patching therapy is limited by a short and early critical period, as well as by poor compliance with prescribed treatment. Temporary pharmacological inactivation of the dominant eye has emerged as a means to rapidly correct the effects of monocular deprivation in animal models. Recovery occurs at older ages, and inactivation causes no apparent damage to neural connections within the primary visual pathway. It is unclear what mechanisms protect synaptic connections serving the inactivated eye. Astrocytes are important for the development and maintenance of synapses throughout the nervous system, and can compensate for a prolonged decrease in neural activity. The aim of the current study was to investigate a possible role for astrocytes in mediating the protection of neural connections following monocular inactivation. A significant increase in immunolabeling for glial fibrillary acidic protein (GFAP), a marker for astrocyte activation, was measured within inactivated-eye layers of the dorsal lateral geniculate nucleus from otherwise normal animals. Elevated levels of GFAP persisted even after the period of inactivation wore off, and GFAP was not significantly elevated following monocular deprivation by lid closure. These results implicate astrocyte activation as a possible mechanism that mediates the safeguarding of neural connections during monocular retinal inactivation. The viability of retinal inactivation as a safe and effective treatment for human amblyopia is facilitated by advancing the understanding of its effects within the visual system.

Neuropathic pain is a debilitating condition caused by damage to the nervous system that results in changes along the pain pathway that lead to persistence of the pain sensation. Unremitting pain conditions are associated with maladaptive plasticity, disruption of neuronal activity that favours excitation over inhibition, and engagement of immune cells. The substantial progress made over the last two decades in the neuroimmune interaction research area points to a mechanistic role of spinal cord microglia, which are resident immune cells of the CNS. Microglia respond to and modulate neuronal activity during establishment and persistence of neuropathic pain states, and microglia-neuron pathways provide targets that can be exploited to attenuate abnormal neuronal activity and provide pain relief.

Substance use has been intertwined with human history for millennia. Throughout the ages, people have consumed various substances for medicinal, spiritual, and recreational reasons, although occasional use differs significantly from substance use disorders (SUDs). Exposure to lifetime stressors constitutes a significant risk factor for both psychiatric disorders and SUD development and relapse. Indeed, hypothalamic-pituitary-adrenal (HPA) axis modulation, alterations in neuroanatomical and neurotransmitter systems, as well as neuroinflammation are common features of stress-related mood disorders and SUDs. In this mini-review, we will explore how stress exposure influences the SUDs' neurobiological basis on different scales-from large neural circuitries to specific molecular mechanisms-and discuss novel targets for potential treatments.

Primary cultures of brainstem tissue can be used to investigate cellular and molecular mechanisms involved in disease pathology and to identify novel therapeutic targets that modulate neuron and glial cell activities. However, preparation of primary cultures from rodent embryos or neonatal animals is labor-intensive, and it can be difficult to produce high-quality consistent cultures. To overcome these issues, cryopreservation can be used to obtain standardized, high-quality stocks of brainstem neuronal and glial cells. We present a simplified cryopreservation method for establishing primary cell cultures of pons and medulla oblongata tissue from Sprague-Dawley neonates, using a 90:10 (v/v) fetal bovine serum/dimethyl sulfoxide cell freezing medium. Cryopreserved brainstem cells stored for up to one year in liquid nitrogen exhibited similar neuronal and glial cell morphology, cell ratios, and viability when compared to fresh cultures. The expression of proteins in neurons and glial cells implicated in pain signaling and central sensitization agreed with their reported subcellular localization. Elevated intracellular calcium levels were observed in neurons and glia in response to ATP. This method for the preparation and cryopreservation of brainstem cells for establishing primary neuron-glia cultures similar to fresh preparations, is straightforward, can be utilized for biochemical, cellular, and molecular studies, increases reproducibility, requires no special equipment or reagents, saves laboratory resources including time and money, reduces the number of animals used in research, and increases flexibility in study design.

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.

Astrocytes are the most abundant type of macroglia in the brain and play crucial roles in regulating neural development and functions. The diverse functions of astrocytes are largely determined by their morphology, which is regulated by genetic and environmental factors. However, whether and how the astrocyte morphology is affected by temperature remains largely unknown. Here we discovered that elevated cultivation temperature (26°C) stimulates Caenorhabditis elegans ventral CEPsh glia endfoot extension during early developmental stages. This extension depends on the activation of glutamate AWC neurons, which inhibit the postsynaptic cholinergic AIY interneurons through glutamate-gated chloride channels, GLC-3 and GLC-4. In responding to the thermosensory signal, the guanyl-nucleotide exchange factor EPHX-1 and Rho GTPase CDC-42/Cdc42 in the glia facilitate the endfoot extension via F-actin assembly. This study elucidates the significant role of thermosensory circuitry in glia morphogenesis and the underlying molecular mechanism.

Despite the advances in detection, diagnosis, and treatments, cancer remains a lethal disease, claiming the lives of more than 600,000 people in the United States alone in 2024. To accelerate the development of new therapeutic strategies with improved responses, significant efforts have been made to develop microfabricated in vitro models of tumor microenvironments (TMEs) that address the limitations of animal-based cancer models. These models incorporate several advanced tissue engineering techniques to better reflect the organ- and patient-specific TMEs. Additionally, microfabricated models integrated with next-generation single-cell omics technologies provide unprecedented insights into patient's cellular and molecular heterogeneity and complexity. This review provides an overview of the recent understanding of cancer development and outlines the key TME elements that can be captured in microfabricated models to enhance their physiological relevance. We highlight the recent advances in microfabricated cancer models that reflect the unique characteristics of their organs of origin or sites of dissemination.

After peripheral nerve injury, the structure of the spinal cord is actively regulated by glial cells, contributing to the chronicity of neuropathic pain. However, the mechanism by which peripheral nerve injury leads to synaptic imbalance remains elusive. Here, we use a pH-reporter system and find that nerve injury triggers a reorganization of excitatory synapses that is influenced by the accumulation of the ganglioside GT1b at afferent terminals. GT1b acts as a protective signal against nerve injury-induced spinal synapse elimination. Inhibition of GT1b-synthesis increases glial phagocytosis of excitatory pre-synapses and reduces excitatory synapses post-injury. In vitro analyses reveal a positive correlation between GT1b accumulation and the frequency of pre-synaptic calcium activity, with GT1b-mediated suppression of glial phagocytosis occurring through SYK dephosphorylation. Our study highlights GT1b's pivotal role in preventing synapse elimination after nerve injury and offers new insight into the molecular underpinning of activity-dependent synaptic stability and glial phagocytosis.

Astrocytes are highly complex cells that mediate critical roles in synapse formation and maintenance by establishing thousands of direct contacts with synapses through their perisynaptic processes. Here, we found that the most common Parkinsonism gene mutation, LRRK2 G2019S, enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), components of the perisynaptic astrocyte processes in a subset of cortical astrocytes. The ERM hyperphosphorylation was accompanied by decreased astrocyte morphological complexity and reduced excitatory synapse density and function. Dampening ERM phosphorylation levels in LRRK2 G2019S mouse astrocytes restored both their morphology and the excitatory synapse density in the anterior cingulate cortex. To determine how LRRK2 mutation impacts Ezrin interactome, we used an in vivo BioID proteomic approach, and we found that astrocytic Ezrin interacts with Atg7, a master regulator of autophagy. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in LRRK2 G2019S astrocytes. Importantly, the Atg7 function is required to maintain proper astrocyte morphology. Our data provide a molecular pathway through which the LRRK2 G2019S mutation alters astrocyte morphology and synaptic density in a brain-region-specific manner.

Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.

The progression of traumatic brain injury (TBI) pathology is significantly influenced by age and involves a complex interplay of glial cells. However, the influence of age on the glial dynamics and their TBI responses remains mostly unexplored. Here, we obtain a comprehensive single-cell transcriptome atlas of three major glial types under the physiological and TBI conditions across four post-embryonic life stages in the zebrafish midbrain optic tectum. We identify a library of glial subtypes and states with specific age-dependent patterns that respond distinctly to TBI. Combining the glial interactome analysis and CRISPR-Cas9-mediated gene disruption, we reveal the essential roles of dla-notch3 and cxcl12a-cxcr4b interactions in the early-larval-stage-specific unresponsiveness of radial astrocytes to TBI and the TBI-induced age-independent recruitment of microglia to injury sites, respectively. Overall, our findings provide the molecular and cellular framework of TBI-induced age-related glial dynamics in vertebrate brains.

The complex morphologies of mature neurons and glia emerge through profound rearrangements of cell membranes during development. Despite being integral components of these membranes, it is unclear whether lipids might actively sculpt these morphogenic processes. By analyzing lipid levels in the developing fruit fly brain, we discover dramatic increases in specific sphingolipids coinciding with neural circuit establishment. Disrupting this sphingolipid bolus via genetic perturbations of sphingolipid biosynthesis and catabolism leads to impaired glial autophagy. Remarkably, glia can obtain sphingolipid precursors needed for autophagy by phagocytosing neurons. These precursors are then converted into specific long-chain ceramide phosphoethanolamines (CPEs), invertebrate analogs of sphingomyelin. These lipids are essential for glia to arborize and infiltrate the brain, a critical step in circuit maturation that when disrupted leads to reduced synapse numbers. Taken together, our results demonstrate how spatiotemporal tuning of sphingolipid metabolism during development plays an instructive role in programming brain architecture.

Brain sphingolipids (SLs) remodel to very long-chain species during circuit maturation Glial autophagy requires de novo SL biosynthesis coordinated across neurons and glia Glia evade a biosynthetic blockade by phagolysosomal salvage of neuronal SLsCeramide Phosphoethanolamine is critical for glial infiltration and synapse density.

Cadmium (Cd), a neurotoxic metal, is associated with the development of neurological disorders. This study investigated the neuroprotective effects of Luteolin against Cd-induced toxicity in cultured cells and mouse models. Our findings demonstrate that Luteolin protects hippocampal neurons from Cd toxicity and mitigates Cd-triggered inflammatory responses in microglial BV2 cells. In Cd-exposed mice, symptoms such as weight loss, motor retardation, multi-organ damage, and cognitive deficits were observed. Remarkably, Luteolin treatment reversed these effects, repaired organ damage, and restored learning and memory abilities. Mechanistically, Cd toxicity induced significant upregulation of pro-inflammatory factors and neuroinflammation in the hippocampus and prefrontal cortex, including elevated glial cell markers (IBA1, GFAP, and CD68) and reduced neuronal marker MAP2. Luteolin counteracted these adverse effects by inhibiting the Notch1/Hes1 inflammatory signaling axis and restoring the BDNF-TrkB/AKT1 signaling axis, thereby promoting neuronal survival. These results highlight the potential of Luteolin as a natural neuroprotective agent against Cd-induced neurotoxicity, offering a promising therapeutic strategy for mitigating Cd-related neurological damage.

Neuroplasticity, the ability of the nervous system to adapt structurally and functionally in response to environmental interactions and injuries, is a cornerstone of recovery in the central (CNS) and peripheral nervous systems (PNS). This review explores the mechanisms underlying neuroplasticity, focusing on the dynamic roles of cellular and molecular processes in recovery from nervous system injuries. Key cellular players, including Schwann cells, oligodendrocytes, and neural stem cells, are highlighted for their contributions to nerve repair, myelination, and regeneration. Advances in therapeutic interventions, such as electrical stimulation, bioluminescent optogenetics, and innovative nerve grafting techniques, are discussed alongside their potential to enhance recovery and functional outcomes. The molecular underpinnings of plasticity, involving synaptic remodeling, homeostatic mechanisms, and activity-dependent regulation of gene expression, are elucidated to illustrate their role in learning, memory, and injury repair. Integrating emerging technologies and therapeutic approaches with a foundational understanding of neuroplasticity offers a pathway toward more effective strategies for restoring nervous system functionality after injury.

This study investigates whether scutellarin promotes astrocyte polarization in MCAO and OGD models, and its effects on astrocyte-microglia, astrocyte-neuron interactions, and the PI3K-Akt pathway in neuroprotection. We used an experimentally induced cerebral ischemia rat model and OGD-stimulated TNC1 cell model. Using western blot, RT-qPCR and immunofluorescence, we show a noticeable increase in the expression of A2 astrocyte markers and a downregulation of A1 astrocyte markers in activated astrocytes, both in vivo and in vitro. Remarkably, after the treatment of scutellarin, OGD-stimulated TNC1 cells markedly downregulated M1 microglia markers and apoptosis factors in PC12 cells, while upregulating M2 microglia markers and anti-apoptosis factor Bcl2. Therefore, it is suggested that scutellarin can promote the polarization of activated astrocyte from the A1 to the A2 phenotype. Meanwhile, there is indeed a crosstalk between astrocytes-microglia and astrocytes-neurons, and astrocytes treated with scutellarin can promote M2 polarization of microglia and neuronal apoptosis. More importantly, based on the results of transcriptome sequencing, we used TNC1-pik3r1-siRNA cell model and pcDNA3.1 ( +)-pik3r1-TNC1 cell model to investigate the effect of the PI3K-Akt signaling pathway on the polarization of astrocyte and their crosstalk. Scutellarin promotes the A2 polarization, M2 polarization, and anti-apoptosis in astrocyte crosstalk by concomitantly enhancing the PI3K-Akt signaling pathway. This is strongly supported by observations in TNC1 astrocyte in TNC1-pik3r1-siRNA cell model, where the expression of A2 markers was decreased. Conversely, in the pcDNA3.1 ( +)-pik3r1-TNC1 cell model, expression was increased. In light of the above, the PI3K-Akt signaling pathway is considered a potential therapeutic target.

Adult neurogenesis in cartilaginous fish remains a relatively unexplored area, particularly in terms of comparative analysis. This process, defined as the ability of specialized stem cells to generate new functional neurons, has gained prominence due to its relevance in neurodegenerative disease research and regenerative medicine. However, there is an ongoing discussion about when and where it first appeared. Evidence of adult neurogenesis in both teleosts and mammals highlights significant differences, such as the number of newly formed cells and the brain regions involved. Investigating additional cartilaginous fish species, which occupy a basal position in vertebrate phylogeny, could provide valuable insights into the ancient origins of this trait and potentially new general knowledge about the adult neurogenesis process. In this study, we combined immunohistochemistry and in situ hybridization to examine neurogenic activity in three brain regions-the telencephalon, mesencephalon, and cerebellum-of two batoid species: Raja asterias and Torpedo ocellata. Immunohistochemical methods were used to identify neurogenic cells by employing markers for cell proliferation (PCNA), mitosis (pH3), glial cells (S100B), and stem cells (Msi1). Additionally, in situ hybridization was performed to detect neural stem cell mRNA for Notch1, Notch3, and Sox2 in the telencephalon and mesencephalon of Raja asterias.

Astrocytes exert multiple functions within the brain, including regulating neuroinflammation and maintaining homeostasis, and the reactive astrocytes are implicated in many neurodegenerative disorders. Imidazoline-2 binding site (I2BS) has been established as a reliable biomarker for precisely quantifying reactive astrocytes. Here, we reported the development of [125I]iodotrazoline ([125I]8), a novel I2BS radioligand with high affinity (Ki = 6.8 nM) and exceptional selectivity over α2-adrenoceptors (>1400 folds). In vitro autoradiography (ARG) using rat brain sections revealed a heterogeneous distribution of [125I]8, with high signals in the medulla, midbrain, pons, and hypothalamus. Pretreatment with unlabeled I2BS-selective ligands, BU224 and FTIMD, reduced the binding by >30%, indicating high in vitro specificity for I2BS. Ex vivo ARG results confirmed this distribution pattern in the rat brain. Biodistribution results in mice demonstrated a rapid brain uptake of [125I]8 (3.35% ID/g at 2 min postinjection) with slow washout. Metabolite analysis exhibited the desirable biostability of [125I]8 in the rat brain. Altogether, this work provides a new 125I-labeled radioligand featuring a novel 2-trans-styryl-imidazoline scaffold, which shows significant specificity binding for I2BS in vitro, serving as a valuable tool for I2BS detection and astrocyte-related pathology research.

The interplay between the nervous and immune systems is well documented in the context of adult physiology and disease. Recent advances in understanding immune cell development have highlighted a significant interaction between neural lineage cells and microglia, the resident brain macrophages, during developmental stages. Throughout development, particularly from the embryonic to postnatal stages, diverse neural lineage cells are sequentially generated, undergo fate determination, migrate dynamically to their appropriate locations while maturing, and establish connections with their surroundings to form neural circuits. Previous studies have demonstrated that microglia contribute to this highly orchestrated process, ensuring the proper organization of brain structure. These findings underscore the need to further investigate how microglia behave and function within a broader framework of neurodevelopment. Importantly, recent epidemiological studies have suggested that maternal immune activation (MIA), triggered by various factors, such as viral or bacterial infections, environmental stressors, or other external influences, can affect neurogenesis and neural circuit formation, increasing the risk of neurodevelopmental disorders (NDDs) in offspring. Notably, many studies have revealed that fetal microglia undergo significant changes in response to MIA. Given their essential roles in neurogenesis and vascular development, inappropriate activation or disruption of microglial function may impair these critical processes, potentially leading to abnormal neurodevelopment. This review highlights recent advances in rodent models and human studies that have shed light on the behaviors and multifaceted roles of microglia during brain development, with a particular focus on the embryonic stage. Furthermore, drawing on insights from rodent MIA models, this review explores how MIA disrupts microglial function and how such disturbances may impair brain development, ultimately contributing to the onset of NDDs.

The hypothalamus, an "ancient" subcortical brain structure, maintains physiological homeostasis and controls native behaviors. The evolution of homeostatic regulation and behavioral control in mammals may rely on adaptable neuronal identity establishment but conserved neural patterning mechanisms during neurodevelopment. Here, we combined single-cell, single-nucleus, and spatial transcriptomic datasets to map the spatial patterning of diverse progenitor domains and reconstruct their neurogenic lineages in the developing human and mouse hypothalamus. While the regional organizers orchestrating neural patterning are conserved between primates and rodents, we identified a human-enriched neuronal subtype and found a substantial increase in neuromodulatory gene expression among human neurons. Furthermore, cross-species comparison demonstrated a potential redistribution of two neuroendocrine neuronal subtypes and a shift in inter-transmitter and transmitter-peptide coupling within hypothalamic dopamine neurons. Together, our study lays a critical foundation for understanding cellular development and evolution of the mammalian hypothalamus.

Neuro-immune interactions within barrier organs, such as lung, gut, and skin, are crucial in regulating tissue homeostasis, inflammatory responses, and host defence. Our rapidly advancing understanding of peripheral neuroimmunology is transforming the field of barrier tissue immunology, offering a fresh perspective for developing therapies for complex chronic inflammatory disorders affecting barrier organs. However, most studies have primarily examined interactions between the peripheral nervous system and the immune system from a neuron-focused perspective, while glial cells, the nonneuronal cells of the nervous system, have received less attention. Glial cells were long considered as mere bystanders, only supporting their neuronal neighbours, but recent discoveries mainly on enteric glial cells in the intestine have implicated these cells in immune-regulation and inflammatory disease pathogenesis. In this review, we will highlight the bi-directional interactions between peripheral glial cells and the immune system and discuss the emerging immune regulatory functions of glial cells in barrier organs.

Obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 h of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Understanding more precisely the kinetics of glial activation of two major brain cells (astrocytes and microglia) and their impact on eating behavior could prevent obesity and offer new prospects for therapeutic treatments. To understand the mechanisms pertaining to obesity-related neuroinflammation, we developed a fully automated algorithm, NutriMorph. Although some algorithms were developed in the past decade to detect and segment cells, they are highly specific, not fully automatic, and do not provide the desired morphological analysis. Our algorithm copes with these issues and performs the analysis of cells images (here, microglia of the hypothalamic arcuate nucleus), and the morphological clustering of these cells through statistical analysis and machine learning. Using the k-Means algorithm, it clusters the microglia of the control condition (healthy mice) and the different states of neuroinflammation induced by high-fat diets (obese mice) into subpopulations. This paper is an extension and re-analysis of a first published paper showing that microglial reactivity can already be seen after few hours of high-fat diet (Cansell et al., 2021 [5]). Thanks to NutriMorph algorithm, we unravel the presence of different hypothalamic microglial subpopulations (based on morphology) subject to proportion changes in response to already few hours of high-fat diet in mice.

How animal brains evolve to support ecological specialization is poorly understood. A recent PLOS Biology study reveals that glial cells show the most dramatic molecular and cellular changes in the brains of fruit flies adapted to a toxic niche, highlighting their underappreciated role in brain evolution.

Astrocytes are the most abundant type of glial cell in the central nervous system. Upon injury and inflammation, astrocytes become reactive and undergo morphological and functional changes. Depending on their phenotypic classification as A1 or A2, reactive astrocytes contribute to both neurotoxic and neuroprotective responses, respectively. However, this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries. Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles, which emphasizes the heterogeneous nature of their reactivity. Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types, releasing cytokines, and influencing the immune response. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior, as evidenced by in silico , in vitro , and in vivo results. In astrocytes, inflammatory cues trigger a cascade of molecular events, where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses. Here, we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation. We highlight the involvement of various signaling pathways that regulate astrocyte reactivity, including the PI3K/AKT/mammalian target of rapamycin (mTOR), α v β 3 integrin/PI3K/AKT/connexin 43, and Notch/PI3K/AKT pathways. While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage, evidence suggests that activating this pathway could also yield beneficial outcomes. This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation. The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior. The findings should then be validated using in vivo models to ensure real-life relevance. The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage, although further studies are required to fully comprehend its role due to varying factors such as different cell types, astrocyte responses to inflammation, and disease contexts. Specific strategies are clearly necessary to address these variables effectively.

White matter injury (WMI), the most common type of brain damage in infants born preterm, is characterized by failure in oligodendrocyte progenitor cell maturation and myelination, thereby contributing to long-term neurological impairments. Regrettably, effective therapies for promoting remyelination and improving function are currently lacking for this growing population affected by WMI. Recombinant human fibroblast growth factor (rhFGF) 21 modulated microglial activation and then ameliorated brain damage and improved neurological deficits in several central nervous system diseases. However, the effects of rhFGF21 treatment on WMI in preterm infants remain uncertain. In this study, we established an in vivo mouse model of cerebral hypoxia-ischemia (HI)-induced brain WMI and an in vitro model using oxygen-glucose deprivation (OGD)-treated HMC3 cells to investigate the neuroprotective effects of rhFGF21 against WMI and elucidated the potential mechanism. Our findings demonstrated that administration of rhFGF21 significantly ameliorated the retardation of oligodendrocyte differentiation, promoted myelination, and mitigated axonal deficits, synaptic loss, and GFAP scarring, thereby improving lifelong cognitive and neurobehavioral dysfunction associated with WMI. Moreover, rhFGF21 modulated microglial polarization, promoted a shift from the M1 to the M2 microglial phenotype, and suppressed microglial activation, thus ameliorating inflammatory response and oxidative stress. Additionally, rhFGF21 treatment significantly inhibited the HMGB1/NF-κB pathway linked to inflammation, and activated the NRF2 pathway associated with oxidative stress through the upregulation of PPAR-γ. Importantly, the beneficial effects of rhFGF21 on HI-induced WMI and microglial activation were dramatically inhibited by PPAR-γ antagonist and its siRNA. Our findings provide compelling evidence that rhFGF21 treatment mitigated the inflammatory response and oxidative stress through the modulation of microglial polarization via the PPAR-γ-mediated HMGB1/NF-κB pathway and the NRF2 pathway, respectively, contributes to neuroprotection and the amelioration of WMI in neonatal mice. Thus, rhFGF21 represents a promising therapeutic agent for the treatment of neonatal WMI.

Neural circuits consisting of neurons and glial cells help to establish all functions of the CNS. Microglia, the resident immunocytes of the CNS, are endowed with UDP-sensitive P2Y6 receptors (P2Y6Rs) which regulate phagocytosis/pruning of excessive synapses during individual development and refine synapses in an activity-dependent manner during adulthood. In addition, this type of receptor plays a decisive role in primary (Alzheimer's disease, Parkinson's disease, neuropathic pain) and secondary (epilepsy, ischemic-, mechanical-, or irradiation-induced) neurodegeneration. A whole range of microglial cytokines controlled by P2Y6Rs, such as the interleukins IL-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α), leads to neuroinflammation, resulting in neurodegeneration. Hence, small molecular antagonists of P2Y6Rs and genetic knockdown of this receptor provide feasible ways to alleviate inflammation-induced neurological disorders but might also interfere with the regulation of the synaptic circuitry. The present review aims at investigating this dual role of P2Y6Rs in microglia, both in shaping neural circuits by targeted phagocytosis and promoting neurodegenerative illnesses by fostering neuroinflammation through multiple transduction mechanisms.

Tissues maintain their function through interaction with microenvironment. During aging, both hair follicles and blood vessels (BV) in skin undergo degenerative changes. However, it is elusive whether the changes are due to intrinsic aging changes in hair follicles or blood vessels respectively, or their interactions.

To explore how hair follicles and blood vessels interact to regulate angiogenesis and hair regeneration during aging.

Single-cell RNA-sequencing (scRNA-seq) analyses were used to identify the declined ability of dermal papilla (DP) and endothelial cells (ECs) during aging. CellChat and CellCall were performed to investigate interaction between DP and ECs. Single-cell metabolism (scMetabolism) analysis and iPATH were applied to analyze downstream metabolites in DP and ECs. Hair-plucking model and mouse cell organoid model were used for functional studies.

During aging, distance and interaction between DP and ECs are decreased. DP interacts with ECs, with decreased EDN1-EDNRA signaling from ECs to DP and CTF1-IL6ST signaling from DP to ECs during aging. ECs-secreted EDN1 binds to DP-expressed EDNRA which enhances Taurine (TA) metabolism to promote hair regeneration. DP-emitted CTF1 binds to ECs-expressed IL6ST which activates alpha-linolenic acid (ALA) metabolism to promote angiogenesis. Activated EDN1-EDNRA-TA signaling promotes hair regeneration in aged mouse skin and in organoid cultures, and increased CTF1-IL6ST-ALA signaling also promotes angiogenesis in aged mouse skin and organoid cultures.

Our finding reveals reciprocal interactions between ECs and DP. ECs releases EDN1 sensed by DP to activate TA metabolism which induces hair regeneration, while DP emits CTF1 signal received by ECs to enhance ALA metabolism which promotes angiogenesis. Our study provides new insights into mutualistic cellular crosstalk between hair follicles and blood vessels, and identifies novel signaling contributing to the interactions of hair follicles and blood vessels in normal and aged skin.

Programmed cell death protein 1 (PD-1) and its primary ligand PD-L1 are integral components of a significant immune checkpoint pathway, widely recognized for its central role in cancer immunotherapy. However, emerging evidence highlights their broader involvement in both the central and peripheral nervous systems. In this study, we demonstrate that PD-L1/PD-1 signaling in astrocytes during mouse brain development regulates astrocyte maturation and morphogenesis via the MEK/ERK pathway by targeting the downstream effector cysteine and glycine rich protein 1 (CSRP1). This enhanced astrocyte morphological complexity results in increased end-foot coverage of blood vessels. Additionally, aberrant secretion of CSRP1 by astrocytes interacts with oligodendrocyte precursor cells (OPCs) membrane proteins annexin A1 (ANXA1) and annexin A2 (ANXA2), leading to the exclusion of migrating OPCs from blood vessels. This disruption in OPC migration and differentiation results in abnormal myelination and is associated with cognitive deficits in the mice. Our results provide critical insights into the function of PD-L1/PD-1 signaling in astrocyte-OPC interactions and underscore its relevance to glial cell development and pathogenesis in neurodevelopmental disorders.

Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.

Neuroinflammation is a critical factor in the pathogenesis of various neurodegenerative and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder. Psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT), have demonstrated promising therapeutic effects on neuroinflammation, primarily through interactions with serotonin (5-HT) receptors, particularly the 5-HT2A receptor. Activation of these receptors by psychedelics modulates the production of pro-inflammatory cytokines, regulates microglial activity, and shifts the balance between neurotoxic and neuroprotective metabolites. Additionally, psychedelics affect critical signaling pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and mechanistic target of rapamycin (mTOR) pathways, promoting neuroplasticity and exerting anti-inflammatory effects. Beyond the serotonergic system, other neurotransmitter systems-including the glutamatergic, dopaminergic, noradrenergic, gamma-aminobutyric acid (GABAergic), and cholinergic systems-also play significant roles in mediating the effects of psychedelics. This review examines the intricate mechanisms by which psychedelics modulate neuroinflammation and underscores their potential as innovative therapeutic agents for treating neuroinflammatory and neuropsychiatric disorders.

Brain metastases (BMs) are a relatively common and severe complication in advanced non-small cell lung cancer (NSCLC), significantly affecting patient prognosis. Metastatic tumor cells can alter the brain tumor microenvironment (TME) to promote an immunosuppressive state, characterized by reduced infiltration of tumor-infiltrating lymphocytes (TILs), diminished expression of programmed death-ligand 1 (PD-L1), and changes in other proinflammatory factors and immune cell populations. Microglia, the resident macrophages of the brain, play a pivotal role in modulating the central nervous system (CNS) microenvironment through interactions with metastatic cancer cells, astrocytes, and infiltrating T cells. The M2 phenotype of microglia contributes to immunosuppression in BM via the activation of signaling pathways such as STAT3 and PI3K-AKT-mTOR. Recent advances have enhanced our understanding of the immune landscape of BMs in NSCLC, particularly regarding immune evasion within the CNS. Current immunotherapeutic strategies, including immune checkpoint inhibitors, have shown promise for NSCLC patients with BM, demonstrating intracranial activity and manageable safety profiles. Future research is warranted to further explore the molecular and immune mechanisms underlying BM, aiming to develop more effective treatments.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as a motor neuron-autonomous disease, increasing evidence indicates a significant role of glial cells-astrocytes, microglia, oligodendrocytes, and Schwann cells-in the disease pathophysiology. Astrocytic dysfunction contributes to motor neuron vulnerability through impaired calcium homeostasis, disrupted synaptic integrity, and neurotrophic factor deficits. Microglia, through reactive gliosis and complement-mediated synaptic stripping, exacerbate neurodegeneration and neuroinflammation. Oligodendrocytes exhibit impaired differentiation and metabolic support, while Schwann cells display abnormalities in myelination, extracellular matrix composition, and neuromuscular junction maintenance, further compromising motor function. Dysregulation of pathways such as NF-κB, Notch, and JAK/STAT, alongside the upregulation of complement proteins and microRNAs, reinforces the non-cell-autonomous nature of SMA. Despite the advances in SMN-restorative therapies, they do not fully mitigate glial dysfunction. Targeting glial pathology, including modulation of reactive astrogliosis, microglial polarization, and myelination deficits, represents a critical avenue for therapeutic intervention. This review comprehensively examines the multifaceted roles of glial cells in SMA and highlights emerging glia-targeted strategies to enhance treatment efficacy and improve patient outcomes.

The intricate role of the autonomic nervous system (ANS) in regulating cardiac physiology has long been recognized. Aberrant function of the ANS is central to the pathophysiology of cardiovascular diseases. It stands to reason, therefore, that neuroscience-based cardiovascular therapeutics hold great promise in the treatment of cardiovascular diseases in humans. A decade after the inaugural edition, this White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology and pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.