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.

To elucidate the progression pathways of diabetic macular ischemia (DMI) using OCT angiography (OCTA) images and to assess changes in visual acuity (VA) associated with each pathway.

A single-center, prospective case series study.

One hundred fifty-one eyes from 151 patients with a 3-year follow-up period.

We obtained 3 × 3 mm swept-source OCTA images and conducted analyses of en face images within a central 2.5 mm diameter circle. Nonperfusion squares (NPSs) were defined as 15 × 15-pixel squares without retinal vessels. Each eye at baseline and after 3 years was embedded into a 2-dimensional uniform manifold approximation and projection space and assigned to 1 of 5 severity grades-Initial, Mild, Superficial, Moderate, and Severe-using the k-nearest neighbors method. We assessed major transitions (involving ≥4 cases) during 3 years. Subsequent probabilistic analyses enabled the construction of a graphical model, wherein directed arrows represented inferred pathways of DMI progression. From this cohort, 103 eyes of 103 patients who did not receive any ocular treatments during the follow-up period were subsequently evaluated for VA changes.

Inference of DMI progression pathways.

In most cases, NPS counts increased in both the superficial and deep layers. The major transitions between these severity groups at 3 years displayed a unique distribution, and probabilistic analyses suggested a directed graphical model comprising 7 inferred pathways of DMI progression: Initial to Mild, Initial to Superficial, Mild to Superficial, Mild to Moderate, Superficial to Moderate, Superficial to Severe, and Moderate to Severe. Eyes of the Mild and Superficial groups had greater increases in superficial NPS within the central sector than those of the Severe group. Additionally, deep NPS counts within the central sector decreased more in the eyes of the Initial group than in those of the Superficial and Moderate groups. Notably, the eyes of the Superficial and Moderate groups exhibited greater VA deterioration at 3 years compared with those in the Initial group.

A directed graphical model of DMI progression may serve as a useful tool for inferring progression pathways and predicting VA deterioration.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The blood-brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation. It tightly modulates the ion transport and nutrient influx, while restricting the entry of harmful factors, and selectively limiting the migration of immune cells, thereby maintaining brain homeostasis. Despite the well-established association between blood-brain barrier disruption and most neurodegenerative/neuroinflammatory diseases, much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown. Moreover, the role of blood-brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood. This review aims to revisit this concept of "blood-brain barrier breakdown," delving into the most controversial aspects, prevalent challenges, and knowledge gaps concerning the lack of blood-brain barrier integrity. By moving beyond the oversimplistic dichotomy of an "open"/"bad" or a "closed"/"good" barrier, our objective is to provide a more comprehensive insight into blood-brain barrier dynamics, to identify novel targets and/or therapeutic approaches aimed at mitigating blood-brain barrier dysfunction. Furthermore, in this review, we advocate for considering the diverse time- and location-dependent alterations in the blood-brain barrier, which go beyond tight-junction disruption or brain endothelial cell breakdown, illustrated through the dynamics of ischemic stroke as a case study. Through this exploration, we seek to underscore the complexity of blood-brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Multiple studies have shown that permanent functional disabilities caused after nerve damage are mainly due to the limited ability of damaged neurons in the central nervous system (CNS) to regenerate axons and re-establish functional connections. Most axons in the CNS of adult mammals cannot reactivate their intrinsic growth program after injury, making axonal regeneration difficult when damaged. This article provides a systematic review of the response processes following CNS injury and the factors affecting repair and regeneration, focusing on the molecular mechanisms that regulate the regeneration of damaged axons, in hopes of offering new insights for the repair of CNS injuries.

Ischemic stroke is one of the major causes of death and disability in adults, bringing a significant economic burden to the society and families. Despite significant advancements in stroke treatment, focusing solely on neurons is insufficient for improving disease progression and prognosis. Astrocytes are the most ubiquitous cells in the brain, and they undergo morphological and functional changes after brain insults, which has been known as astrocyte reactivity. Transcriptomics have shown that reactive astrocytes (RA) are heterogeneous, and they can be roughly classified into neurotoxic and neuroprotective types, thereby affecting the development of central nervous system (CNS) diseases. However, the relationship between stroke and reactive astrocyte heterogeneity has not been fully elucidated, and regulating the heterogeneity of astrocytes to play a neuroprotective role may provide a new perspective for the treatment of stroke. Here we systematically review current advancements in astrocyte heterogeneity following ischemic stroke, elucidate the molecular mechanisms underlying their activation, and further summarize promising therapeutic agents and molecular targets capable of modulating astrocyte heterogeneity.

Long-term neurological dysfunction following stroke significantly impairs patients' quality of life. Ginkgo biloba L (GBL), a traditional Chinese herbal medicine, has shown promise in treating ischemic stroke and related disorders. Diterpene Ginkgolides Meglumine Injection (DGMI), derived from GBL, has demonstrated improved recovery outcomes in stroke patients when administered during the hyperacute phase (HAP) in clinical studies, yet the underlying mechanisms remain elusive.

Utilizing a Transient Middle Cerebral Artery Occlusion (tMCAO) model, we evaluated the effects of DGMI at varying doses and administration times on neurological function, brain injury, and identified key genes/pathways via RNA-seq and bioinformatics analyses, validated by RT-PCR. An in vitro LPS-induced astrocyte activation model was used to evaluate DGMI's anti-inflammatory effects.

DGMI administered during the hyperacute phase (HAP, 0.5 h post-tMCAO) exhibited superior neuroprotection compared to the acute phase (AP, 24 h post-tMCAO) in mice. HAP-DGMI significantly enhanced survival rates, reduced neurological deficit scores, infarct sizes, and neuronal apoptosis, with more pronounced improvements observed on days 3 and 7 post-tMCAO. Transcriptome sequencing revealed that HAP-DGMI more effectively normalized abnormal gene expression profiles, particularly in genes involved in immune and inflammatory pathways, in both motor (M1) and sensory (S1) cortices. Additionally, HAP-DGMI reversed a higher proportion of disease-characteristic pathways compared to AP.

These findings underscore the potential of early HAP intervention with DGMI in enhancing neuroprotection and functional recovery in AIS bymodulating key immune and inflammatory genes and pathways, providing experimental and theoretical support for the clinical application of DGMI.

Chronic pain profoundly disrupts patients' daily lives and places a heavy burden on their families. Tanshinol Borneol Ester (DBZ), a novel synthetic derivative, has demonstrated anti-inflammatory and anti-atherosclerotic effects, yet its impact on the central nervous system (CNS) remains largely unexplored. This study systematically examines the CNS effects of DBZ through a combination of in vivo, in vitro, network pharmacology, and molecular docking approaches. In vivo, we utilized a mouse model of chronic inflammation induced by complete Freund's adjuvant (CFA) to evaluate DBZ's influence on pain, anxiety-like behaviors, and its modulation of inflammatory and oxidative stress markers within the anterior cingulate cortex (ACC). In vitro studies on primary mouse astrocytes assessed DBZ's effects on cell viability and inflammatory marker expression. Network pharmacology was employed to elucidate DBZ's potential molecular targets and pathways, While molecular docking provides valuable docking confirmed its interactions with key components of the JAK2-STAT3 signaling pathway. Our findings demonstrate that DBZ effectively mitigates CFA-induced chronic pain and anxiety-like behaviors. It significantly suppresses astrocytes activation, reduces levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, and diminishes oxidative stress markers such as ROS and MDA, while enhancing SOD levels. Moreover, DBZ modulates excitatory synaptic proteins and the JAK2-STAT3 signaling pathway in the ACC, suggesting its role in neuroprotection. These results position DBZ as a promising candidate for the treatment of chronic pain and anxiety, offering a potential foundation for the development of new therapeutic agents.

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.

Spinal cord injury (SCI) constitutes a profound central nervous system disorder characterized by significant neurological dysfunction and sensory loss below the injury site. SCI elicits a multifaceted cellular response in which the proliferation of reactive astrocytes and the ensuing diversity in their functions and phenotypes play pivotal roles within the injury microenvironment, especially during the secondary phases of the condition. This review explores the activation and heterogeneity of astrocytes following SCI. It underscores the necessity of delineating the heterogeneity among reactive astrocyte subpopulations throughout the secondary injury phase of SCI. Developing therapeutic strategies that capitalize on the beneficial properties of certain reactive astrocyte subpopulations while mitigating the adverse effects of others could have profound implications for future clinical management of SCI.

The neurovascular unit (NVU) is composed of neurons, glial cells, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix. The NVU controls the permeability of the blood-brain barrier (BBB) and protects the brain from harmful blood-borne and endogenous and exogenous substances. Among these, neurons transmit signals, astrocytes provide nutrients, microglia regulate inflammation, and BMECs and pericytes strengthen barrier tightness and coverage. These cells, due to their physical structure, anatomical location, or physiological function, maintain the microenvironment required for normal brain function. In this review, the BBB structure and mechanisms are examined to obtain a better understanding of the factors that influence BBB permeability. The findings may aid in safeguarding the BBB and provide potential therapeutic targets for drugs affecting the central nervous system.

Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system. Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons. Despite the recognition of potential heterogeneity in mature oligodendrocyte function, a comprehensive summary of mature oligodendrocyte diversity is lacking. We delve into early 20 th -century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes. Indeed, recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences. Furthermore, modern molecular investigations, employing techniques such as single cell/nucleus RNA sequencing, consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region. Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis, Alzheimer's disease, and psychiatric disorders. Nevertheless, caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations. Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity. Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species, sex, central nervous system region, age, and disease, hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.

Epilepsy is a brain disorder characterized by alterations in the neuronal environment that predispose individuals to spontaneous and recurrent epileptic seizures. One of the major challenges in recent years has been the accurate diagnosis and appropriate pharmacological management of the condition. When seizures are not well controlled, individuals may develop status epilepticus, a condition with an unfavorable prognosis that requires immediate attention and treatment. Furthermore, approximately 30 % of patients are refractory to conventional treatments. In this study, we evaluated the effects of prednisolone in an acute animal model of epileptic seizures induced by pentylenetetrazole (PTZ) at doses of 1 mg/kg and 5 mg/kg. We analyzed the severity of epileptic seizures and the modulation of pro-inflammatory cytokines in treated animals. Four treatment groups were used: saline solution, diazepam (2 mg/kg), prednisolone (1 mg/kg), and prednisolone (5 mg/kg). The animals were treated, and after 30 min, PTZ (60 mg/kg) was administered. Levels of the cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus and prefrontal cortex. Animals treated with prednisolone exhibited less severe epileptic seizures compared to the saline group, along with reduced levels of pro-inflammatory cytokines, particularly in the prefrontal cortex. Some animals were also assessed using EEG. Consistent with our previous studies, prednisolone demonstrated an anticonvulsant effect at doses of 1 mg/kg and 5 mg/kg in the acute PTZ-induced seizure model.

Obesity and depression are likely to co-occur. However, there are few reports on the relationship between obesity and depression. We aimed to investigate the effect of high-fat diet combined with chronic restraint stress on depressive-like behaviors, focusing on the phenotypic transformation of astrocytes. Male C57BL/6 mice were randomly divided into four equal groups: control, high-fat diet (HFD), chronic restraint stress (CRS) and HFD + CRS groups. They were subjected to an 8-week high-fat diet and 3-week restraint stress stimulation. In vitro, palmitic acid (PA) and corticosterone (Cort) were used to mimic HFD and CRS respectively on C8-D1A astrocytes. Our results showed that HFD aggravates anxiety and depression-like behaviors and learning and memory deficits induced by CRS, as reflected by sucrose preference, forced swimming test, tail suspension tests, open field test and the Morris water maze. The expression level of C3 protein in the hippocampus of the mice in the HFD + CRS group was three times that of the CON group. HFD combined with CRS significantly inhibited the protein expression of the Wnt/β-catenin signaling pathway. Consistent with the results of animal experiments, the results of the in vitro experiments showed that the protein expressions of A1 astrocytes marker in C8-D1A astrocytes were much higher in the PA + Cort group. And the protein expressions the Wnt/β-catenin signaling pathway-associated proteins were obviously lower in the PA + Cort group. Furthermore, Wnt/β-catenin pathway agonist SKL2001 treatment decreased the A1 astrocytes marker expressions in C8-D1A astrocytes, and improves the anxiety and depression-like behaviors and learning and memory deficits in HFD mice combined with CRS. This study suggested that HFD combined with CRS could promote the transformation of astrocytes into A1 type and the Wnt/β-catenin signaling pathway may be involved in this process.

Evidence for involvement of astrocytes in several neurodegenerative disorders and in drug addiction has been emerging over the last two decades, but only in recent years have astrocytes been investigated for their roles in alcohol use disorder (AUD). As a result, there is a need to evaluate existing preclinical literature supporting involvement of astrocytes in the effects of alcohol exposure. Here we review emerging evidence about responses of astrocytes to alcohol, and the contributions of astrocytes to the development of AUD. We review studies of single-cell RNA sequencing with a focus on alcohol and astrocyte heterogeneity, astrocyte reactivity, and the role of astrocytes in remodeling the extracellular matrix. Effects of alcohol on astrocyte-modulated synaptic transmission are also discussed emphasizing studies never reviewed before. Since astrocytes play essential roles in brain development, we review recent research on the role of astrocytes in fetal alcohol spectrum disorders (FASD) which may also shed light on fetal development of psychiatric disorders that have a high prevalence in individuals affected by FASD. Finally, this review highlights gaps in knowledge about astrocyte biology and alcohol that need further research. Particularly, the dire need to identify astrocyte subpopulations and molecules that are susceptible to alcohol exposure and may be targets for therapeutic intervention.

Traumatic brain injury (TBI) induces profound functional heterogeneity in astrocytes, yet the regulatory mechanisms underlying this diversity remain poorly understood. In this study, we analyzed single-cell RNA sequencing data from the cortex and hippocampus of TBI mouse models to characterize astrocyte subtypes and their functional dynamics. We identified two major reactive subtypes: A1 astrocytes, enriched in inflammatory response, synaptic regulation, and neurodegenerative disease-related pathways; and A2 astrocytes, enriched in lipid metabolism, extracellular matrix (ECM) remodeling, and phagosome formation pathways. These functional differences were consistently observed across datasets with varying injury severities. Notably, adhesion-related pathways-including gap junctions, adherens junctions, and calcium-dependent adhesion-showed significant subtype-specific expression patterns and temporal shifts. Pseudotime trajectory analysis further suggested a potential transition between A1 and A2 states, accompanied by dynamic regulation of adhesion-related genes. Our findings highlight the complex and context-dependent roles of astrocytes in TBI and propose cell adhesion as a key modulator of astrocyte functional polarization.

Pericytes are contractile cells of the microcirculation that participate in wound healing after spinal cord injury (SCI). Thus far, the extent to which pericytes cause or contribute to axon growth and regeneration failure after SCI remains controversial. Here, we found that SCI leads to profound changes in vasculature architecture and pericyte coverage. We demonstrated that pericytes constrain sensory axons on their surface, causing detrimental structural and functional changes in adult dorsal root ganglion neurons that contribute to axon regeneration failure after SCI. Perhaps more excitingly, we discovered that in vivo programming of adult pericytes via local administration of platelet-derived growth factor BB (PDGF-BB) effectively promotes axon regeneration and recovery of hindlimb function by contributing to the formation of cellular bridges that span the lesion. Ultrastructural analysis showed that PDGF-BB induced fibronectin fibril alignment and extension, effectively converting adult pericytes into a permissive substrate for axon growth. In addition, PDGF-BB localized delivery positively affects the physical and chemical nature of the lesion environment, thereby creating more favorable conditions for SCI repair. Thus, therapeutic manipulation rather than wholesale ablation of pericytes can be exploited to prime axon regeneration and SCI repair.

Astrocytes in the spinal cord dorsal horn (SDH) play a pivotal role in synaptic transmission and neuropathic pain. However, the precise classification of SDH astrocytes in health and disease remains elusive. Here, we reveal Gpr37l1 as a marker and functional regulator of spinal astrocytes. Through single-nucleus RNA sequencing, we identified Gpr37l1 as a selective G-protein-coupled receptor (GPCR) marker for spinal cord astrocytes. Notably, SDH displayed reactive astrocyte phenotypes and exacerbated neuropathic pain following nerve injury combined with Gpr37l1 deficiency. In naive animals, Gpr37l1 knockdown in SDH astrocytes induces astrogliosis and pain hypersensitivity, while Gpr37l1-/- mice fail to recover from neuropathic pain. GPR37L1 activation by maresin 1 increased astrocyte glutamate transporter 1 (GLT-1) activity and reduced spinal EPSCs and neuropathic pain. Selective overexpression of Gpr37l1 in SDH astrocytes reversed neuropathic pain and astrogliosis after nerve injury. Our findings illuminate astrocyte GPR37l1 as an essential negative regulator of pain, which protects against neuropathic pain through astrocyte signaling in SDH.

How the human brain develops and what goes awry in neurological disorders represent two long-lasting questions in neuroscience. Owing to the limited access to primary human brain tissue, insights into these questions have been largely gained through animal models. However, there are fundamental differences between developing mouse and human brain, and neural organoids derived from human pluripotent stem cells (hPSCs) have recently emerged as a robust experimental system that mimics self-organizing and multicellular features of early human brain development. Controlled integration of multiple organoids into assembloids has begun to unravel principles of cell-cell interactions. Moreover, patient-derived or genetically engineered hPSCs provide opportunities to investigate phenotypic correlates of neurodevelopmental disorders and to develop therapeutic hypotheses. Here, we outline the advances in technologies that facilitate studies by using assembloids and summarize their applications in brain development and disease modeling. Lastly, we discuss the major roadblocks of the current system and potential solutions.

Following spinal cord injury (SCI), blood-borne monocytes infiltrate the spinal cord, differentiate into macrophages, and dominate the lesion site. Inflammatory responses mediated by macrophages determine nerve regeneration and functional recovery after SCI. Tauroursodeoxycholic acid (TUDCA) shows a neuroprotective effect in different SCI animal models. However, the underlying mechanism of TUDCA regulating monocytes/macrophages to impact nerve regeneration after SCI has not been elucidated clearly. This study aims to investigate the effect of TUDCA on monocyte/macrophage distribution and nerve regeneration in the subacute stage of SCI.

Transwell analysis, Bromodeoxyuridine (BrdU) staining, and TUNEL staining were performed to evaluate the effect of TUDCA on regulating the inflammatory response to impact spinal neural stem cells (NSCs) proliferation and migration, spinal neuron survival, and axon degeneration in vitro. H&E staining, RNA sequencing, and a series of immunofluorescent staining were performed to investigate the pathological progress, gene expression changes, monocytes/macrophages distribution, and nerve regeneration after TUDCA treatment in SCI mice.

We found TUDCA restored spinal NSCs migration and proliferation and reduced spinal NSCs and neurons apoptosis and axon degeneration by regulating inflammatory response in vitro. TUDCA treatment promoted wound healing, down-regulated genes related to inflammatory response, and up-regulated genes related to spinal cord development in SCI mice.

Our study provided evidence that TUDCA treatment regulated monocyte/macrophage distribution and improved the microenvironment to promote nerve regeneration in SCI mice.

Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder.

Hypertension is a major risk factor for cerebrovascular diseases due to its damaging effects on the blood-brain barrier (BBB) and associated pathologies. Oxidative stress-induced endothelial damage plays a critical role in BBB disruption, potentially leading to cognitive impairment and neurodegeneration. In this study, we investigated the protective effects of two essential trace elements, zinc (Zn) and selenium (Se), against oxidative stress in human brain endothelial cells (HBCE5i) exposed to hypertensive shear stress. Using an innovative millifluidic system (LiveBox2), which allows for the precise simulation of continuous flow conditions, we replicated the hemodynamic forces associated with hypertension.

Cells were treated with ZnCl2 (5-50 µM) or Na2SeO3 (50-500 nM) at concentrations selected based on previous studies and confirmed by cytotoxicity assays.

Our results demonstrated that shear stress significantly altered the localization of the tight junction protein zonula occludens-1 (ZO-1) and induced the nuclear translocation of the transcription factor NRF2, a hallmark of oxidative stress. Importantly, treatment with 10 µM ZnCl2 preserved ZO-1 membrane localization and prevented NRF2 translocation, as confirmed by quantitative image analysis. In contrast, Na2SeO3 did not provide comparable protection, although modest improvements in ZO-1 localization were observed in some replicates.

We discuss potential reasons for selenium's limited efficacy, including differences in bioavailability and cellular uptake. Our findings underscore zinc's promising role as a neurovascular protector and suggest that further investigation into more complex in vitro models and in vivo studies is warranted.

The biphasic dose-response behavior, also known as hormesis, is a characteristic feature of numerous natural products. It is defined by beneficial effects at low concentrations and toxicity at higher doses. This study investigates the hormetic effects of Brosimine B, a flavonoid derived from Brosimum acutifolium, on retinal cell viability under oxidative stress.

To simulate ischemic conditions, we used an oxygen-glucose deprivation (OGD) model. Retinal cells were treated with varying concentrations of Brosimine B, and analyses of cell viability, reactive oxygen species (ROS) production, and antioxidant enzyme activity were performed.

Brosimine B at 10 µM significantly enhanced cell viability and reduced ROS production, likely through modulation of oxidative stress-protective enzymes such as catalase. However, higher concentrations (>10 µM) induced cytotoxic effects. A computational modeling approach using a hormetic (inverted U-shaped) model revealed biologically interpretable parameters, including a peak response at 10.2 µM and a hormetic zone width (σ = 6.5 µM) (R2 = 0.984).

These results confirm that Brosimine B exhibits hormetic neuroprotective effects within a well-defined concentration window, supporting its potential as a therapeutic agent for oxidative stress-related retinal damage. The study highlights the value of computational modeling in optimizing dose-response analyses, offering a framework for refining natural product therapies and predicting toxicological thresholds in pharmacological applications.

A combination of intracellular and extracellular abnormalities of the nervous system, coupled with inflammation and intestinal dysbiosis, form the hallmarks of neurodegenerative diseases (NDDs). While it is difficult to identify the precise order in which these hallmarks manifest in NDDs because of their mutualistic nature, they cumulatively result in nervous or neuronal damage that characterizes neurodegeneration. In this review we discuss the roles of microRNAs (miRNAs) in the maintenance of nervous system homeostasis and their implication for NDDs. We further highlight recent advances in, and limitations of, miRNA therapeutics in NDDs and their future potential.

Intracranial pressure (ICP) is pressure within the cranium, between 5 and 15 mmHg in a normal brain, and is influenced by the dynamic balance between brain tissue, cerebrospinal fluid (CSF) and cerebral blood volume. ICP is vital for cerebral health, impacting outcomes in various neurological conditions. Disruptions, such as cerebral haemorrhage, hydrocephalus and malignant hypertension, can lead to elevated ICP, a dangerous condition known as intracranial hypertension (IH). Systemic hypertension significantly impacts cerebral health by causing microvascular damage, dysfunction of the blood-brain barrier (BBB) and impairment of intracranial compliance (ICC). This increases the risk of IH), cerebral ischaemia, neuroinflammation and lacunar infarction, further worsening neurological dysfunction. This review describes the complex relationship between hypertension and ICP regulation, focusing on the mechanisms underlying ICP and ICC adjustments in hypertensive conditions and emphasizing the role of BBB integrity and cerebral blood flow (CBF) dynamics. It discusses how the sympathetic output might change the regulation of CBF and the maintenance of ICP, highlighting how hypertensive conditions can impair this mechanism, increasing the risk of cerebral ischaemia. The neurovascular unit, including astrocytes and microglia, plays a significant role in this process, contributing to IH in hypertensive patients. Understanding the effects of hypertension on ICP and ICC could lead to therapies aimed at preserving BBB integrity, reducing inflammation and improving cerebral compliance, potentially preventing brain dysfunction and reducing stroke risk in hypertensive patients. This review underscores the need for early detection and intervention to mitigate the severe consequences of uncontrolled hypertension on cerebral health.

Chitinase 3-like protein 1 (CHI3L1) is emerging as a promising biomarker for assessing intracranial lesion burden and predicting prognosis in traumatic brain injury (TBI) patients. Following experimental TBI, Chi3l1 transcripts were detected in reactive astrocytes located within the pericontusional cortex. However, the cellular sources of CHI3L1 in response to hemorrhagic contusions in human brain remain unidentified. Hence, we examined a comprehensive collection of histologically defined acute and subacute human cerebral contusions with various surgical intervals using immunohistochemistry, validated through double immunofluorescence for markers such as GFAP, NeuN, MBP, and Iba-1, along with Fluoro-Jade C histofluorescence staining. CHI3L1 was found at meningeal interfaces, showing significant thickening of subpial glial plate. Paradoxically, CHI3L1-positive astrocytes were identified in neuroanatomical locations distant from hemorrhagic foci, where numerous eosinophilic ischemic neurons also exhibited CHI3L1 immunoreactivity. CHI3L1 immunostaining extended into white matter tracts and highlighted various phagocytic or activated microglia forms after delayed surgical decompressions. Given these findings, we advise against using CHI3L1 as a reactive astrogliosis marker due to its expression in multiple cell types, including astrocytes, neurons, oligodendrocytes, ependymocytes, leptomeningeal cells, microglia, and blood vessels. This non-selective response underscores the potential for CHI3L1 elevation patterns in biofluids to reflect the overall lesion burden extent.

Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified PLCη remains largely unknown. We found that PLCη1 is prominently expressed in lateral habenula (LHb) astrocytes. Here, to investigate its physiological role, we generated astrocyte-specific PLCη1 conditional knockout (cKO) mice (Plch1f/f; Aldh1l1-CreERT2). In these cKO mice, we observed a reduction in cellular morphological complexity metrics, such as total process length, as well as a decrease in the passive membrane conductance of LHb astrocytes. Additionally, neuronal function was impacted by the cKO, as the synaptic efficacy and firing rates of LHb neurons increased, while extrasynaptic long-term depression was impaired. Both tonic α-amino-3-hydroxy-5-methyl-4-isoxazolepdlropionic acid receptor/N-methyl-D-aspartate receptor (AMPAR/NMDAR) currents and extracellular glutamate levels were reduced. Interestingly, chemogenetic activation of astrocytes restored the reduced tonic AMPAR/NMDAR currents in cKO mice. Furthermore, LHb astrocyte-specific deletion of PLCη1 via AAV-GFAP-Cre injection induced depressive-like behaviors in mice, which were reversed by chemogenetic activation of LHb astrocytes. Finally, we found that restraint stress exposure decreased Plch1 mRNA expression in the LHb. These findings suggest that PLCη1 could be a potential therapeutic target for depression and highlight the critical role of astrocytes in the etiology of neuropsychiatric disorders.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and emotional instability, primarily resulting from the abnormal accumulation of mutant huntingtin protein. Growing research highlights the role of intestinal microbiota and their metabolites, particularly short-chain fatty acids (SCFAs), in modulating HD progression. SCFAs, including acetate, propionate, and butyrate, are produced by gut bacteria through dietary fiber fermentation and are recognized for their neuroprotective properties. Evidence suggests that SCFAs regulate neuroinflammation, neuronal communication, and metabolic functions within the central nervous system (CNS). In HD, these compounds may support neuronal health, reduce oxidative stress, and enhance blood-brain barrier (BBB) integrity. Their mechanisms of action involve binding to G-protein-coupled receptors (GPCRs) and modulating gene expression through epigenetic pathways, underscoring their therapeutic potential. This analysis examines the significance of SCFAs in HD, emphasizing the gut-brain axis and the benefits of dietary interventions aimed at modifying gut microbiota composition and promoting SCFA production. Further research into these pathways may pave the way for novel HD management strategies and improved therapeutic outcomes.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions with a heterogeneous and multifactorial etiology that is not yet fully understood. Among the various factors that may contribute to ASD development, alterations in the gut microbiota have been increasingly recognized. Microorganisms in the gastrointestinal tract play a crucial role in the gut-brain axis (GBA), affecting nervous system development and behavior. Dysbiosis, or an imbalance in the microbiota, has been linked to both behavioral and gastrointestinal (GI) symptoms in individuals with ASD. The microbiota interacts with the central nervous system through mechanisms such as the production of short-chain fatty acids (SCFAs), the regulation of neurotransmitters, and immune system modulation. Alterations in its composition, including reduced diversity or an overabundance of specific bacterial taxa, have been associated with the severity of ASD symptoms. Dietary modifications, such as gluten-free or antioxidant-rich diets, have shown potential for improving gut health and alleviating behavioral symptoms. Probiotics, with their anti-inflammatory properties, may support neural health and reduce neuroinflammation. Fecal microbiota transplantation (FMT) is being considered, particularly for individuals with persistent GI symptoms. It has shown promising outcomes in enhancing microbial diversity and mitigating GI and behavioral symptoms. However, its limitations should be considered, as discussed in this narrative review. Further research is essential to better understand the long-term effects and safety of these therapies. Emphasizing the importance of patient stratification and phenotype characterization is crucial for developing personalized treatment strategies that account for individual microbiota profiles, genetic predispositions, and coexisting conditions. This approach could lead to more effective interventions for individuals with ASD. Recent findings suggest that gut microbiota may play a key role in innovative therapeutic approaches to ASD management.

Radiotherapy is one of the primary modalities for oncologic treatment and has been utilized at least once in over half of newly diagnosed cancer patients. Cranial radiotherapy has significantly enhanced the long-term survival rates of patients with brain tumors. However, radiation-induced brain injury, particularly hippocampal neuronal damage along with impairment of neurogenesis, inflammation, and gliosis, adversely affects the quality of life for these patients. Astrocytes, a type of glial cell that are abundant in the brain, play essential roles in maintaining brain homeostasis and function. Despite their importance, the pathophysiological changes in astrocytes induced by radiation have not been thoroughly investigated, and no systematic or comprehensive review addressing the effects of radiation on astrocytes and related diseases has been conducted. In this paper, we review current studies on the neurophysiological roles of astrocytes following radiation exposure. We describe the pathophysiological changes in astrocytes, including astrogliosis, astrosenescence, and the associated cellular and molecular mechanisms. Additionally, we summarize the roles of astrocytes in radiation-induced impairments of neurogenesis and the blood-brain barrier (BBB). Based on current research, we propose that brain astrocytes may serve as potential therapeutic targets for treating radiation-induced brain injury (RIBI) and subsequent neurological 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.

Background: Astrocytes play a key role in the inflammatory process accompanying various neurological diseases. Extracellular ATP accompanies inflammatory processes in the brain, but its effect on lipid mediators (oxylipins) in astrocytes remains elusive. Metformin is a hypoglycemic drug with an anti-inflammatory effect that has been actively investigated in the context of therapy for neuroinflammation, but its mechanisms of action are not fully elucidated. Therefore, we aimed to characterize the effects of ATP on inflammatory markers and oxylipin profiles; determine the dependence of these effects on the adaptation of astrocytes to high glucose levels; and evaluate the possibility of modulating ATP effects using metformin. Methods: We estimated the ATP-mediated response of primary rat astrocytes cultured at normal (NG, 5 mM) and high (HG, 22.5 mM) glucose concentrations for 48 h before stimulation. Cell responses were assessed by monitoring changes in the expression of inflammatory markers (TNFα, IL-6, IL-10, IL-1β, iNOS, and COX-2) and the synthesis of oxylipins (41 compounds), assayed with ultra-high-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). Intracellular pathways were assessed by analyzing the phosphorylation of p38; ERK MAPK; transcription factors STAT3 and NF-κB; and the enzymes mediating oxylipin synthesis, COX-1 and cPLA2. Results: The stimulation of cells with ATP does not affect the expression of pro-inflammatory markers, increases the activities of p38 and ERK MAPKs, and activates oxylipin synthesis, shifting the profiles toward an increase in anti-inflammatory compounds (PGD2, PGA2, 12-HHT, and 18-HEPE). The ATP effects are reduced in HG astrocytes. Metformin potentiated ATP-induced oxylipin synthesis (11-HETE, PGD2, 12-HHT, 15-HETE, 13-HDoHE, and 15-HETrE), which was predominantly evident in NG cells. Conclusions: Our data provide new evidence showing that ATP induces the release of anti-inflammatory oxylipins, and metformin enhances these effects. These results should be considered in the development of anti-inflammatory therapeutic approaches aimed at modulating astrocyte function in various pathologies.

IL-17A has been implicated as a critical pro-inflammatory cytokine in the pathogenesis of autoimmune and neurodegenerative disorders. Emerging evidence indicates its capacity to activate microglial cells and astrocytes, subsequently inducing the production of inflammatory mediators that exacerbate neuronal injury and functional impairment. Clinical observations have revealed a demonstrated association between IL-17A concentrations and blood-brain barrier (BBB) dysfunction, creating a pathological feedback loop that amplifies neuro-inflammatory responses. Recent advances highlight the cytokine's critical involvement in neurodegenerative disorders through multiple molecular pathways. Therapeutic interventions utilizing monoclonal antibodies (mAbs) against IL-17A or its cognate receptor (IL-17R) have shown promising clinical potential. This review systematically examines the IL-17A-mediated neuro-inflammatory cascades; the mechanistic contributions to neurodegenerative pathology in the established disease models including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and current therapeutic strategies targeting the IL-17A signaling pathways. The analysis provides novel perspectives on optimizing cytokine-directed therapies while identifying the key challenges and research priorities for translational applications in neurodegeneration.

Glial-origin brain tumors, particularly glioblastomas (GBMs), are known for their devastating prognosis and are characterized by rapid progression and fatal outcomes. Despite advances in surgical resection, complete removal of the tumor remains unattainable, with residual cells driving recurrence that is resistant to conventional therapies. The GBM tumor microenviroment (TME) significantly impacts tumor progression and treatment response. In this review, we explore the emerging role of purinergic signaling, especially the P2X7 receptor (P2X7R). Due to its unique characteristics, it plays a key role in tumor progression and offers a potential therapeutic strategy for GBM through TME modulation. We discuss also the emerging role of the P2X4 receptor (P2X4R) as a promising therapeutic target. Overall, targeting purinergic signaling offers a potential approach to overcoming current GBM treatment limitations.

Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETBR) signaling. Using a genetic loss-of-function screen, we identified angiopoietin-2 (Ang-2) as a factor produced by reactive astrocytes in response to ET. In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETBR agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production. To determine astroglial Ang-2 levels in vivo, reactive astrocytes expressing the high affinity glutamate transporter (GLAST, EAAT1) were isolated by magnetic-activated cell sorting 3 days after stroke. Astrocytes obtained from the ipsilateral hemisphere expressed significantly more Ang-2 compared with astrocytes isolated from the contralateral hemisphere, or from cortices of sham-operated (control) mice. Notably, analysis of microglia sorted from CX3CR1-eGFP mice demonstrated increased cell surface expression of Tie-2, the Ang-2 receptor, on cells obtained from ipsilateral versus contralateral tissue. Addition of recombinant Ang-2 to astrocyte-conditioned medium significantly increased the number of SIM-A9 murine microglial cells cultured under hypoxic conditions (1 % oxygen for 48 h). In transgenic GFAP-CreER™-EDNRB-fl/fl mice with stroke, conditional knockout of astroglial ETBR significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67+/CD11b+). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETBR signaling, are important mediators of microglial cell dynamics after stroke.

Recent studies have shown that neuroinflammation and heightened glial activity, particularly astrocyte overactivation, are associated with Alzheimer's disease (AD). Abnormal accumulation of amyloid-beta (Aβ) induces endoplasmic reticulum (ER) stress and activates astrocytes. Artemisinin (ART), a frontline anti-malarial drug, has been found to have neuroprotective properties. However, its impact on astrocytes remains unclear. In this study, we used Aβ1-42 induced astrocyte cultures and 3 × Tg-AD mice as in vitro and in vivo models, respectively, to investigate the effects of ART on AD related astrocyte overactivation and its underlying mechanisms. ART attenuated Aβ1-42-induced astrocyte activation, ER stress, and inflammatory responses in astrocyte cultures by inhibiting IRE1 phosphorylation and the NF-κB pathway, as evidenced by the overexpression of IRE1 WT and IRE1-K599A (kinase activity invalidated), along with application of activators and inhibitors related to ER stress. Furthermore, ART alleviated the detrimental effects and restored neurotrophic function of astrocytes on co-cultured neurons, preventing neuronal apoptosis during Aβ1-42 treatment. In 3 × Tg-AD mice, ART treatment improved cognitive function and reduced astrocyte overactivation, neuroinflammation, ER stress, and neuronal apoptosis. Moreover, ART attenuated the upregulation of IRE1/NF-κB pathway activity in AD mice. Astrocyte-specific overexpression of IRE1 via adeno-associated virus in AD mice reversed the ameliorating effects of ART. Our findings suggest that ART inhibits astrocyte overactivation and neuroinflammation in both in vitro and in vivo AD models by modulating the IRE1/NF-κB signaling pathway, thereby enhancing neuronal functions. This study underscores the therapeutic potential of ART in AD and highlights the significance of modulating the ER stress-inflammatory cycle and normalizing astrocyte-neuron communication.

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.

Astrocytes, the most prevalent type of glial cells, have been found to play a crucial part in numerous physiological functions. By offering metabolic and structural support, astrocytes are vital for the proper functioning of the brain and regulating information processing and synaptic transmission. Astrocytes located in the medial prefrontal cortex (mPFC) are highly responsive to environmental changes and have been associated with the development of brain disorders. One of the primary mechanisms through which the brain responds to environmental factors is epitranscriptome modification. M6-methyladenosine methylation is the most prevalent internal modification of eukaryotic messenger RNA (mRNA), and it significantly impacts transcript processing and protein synthesis. However, the effects of m6A on astrocyte transcription and function are still not well understood. Our research demonstrates that ALKBH5, an RNA demethylase of m6A found in astrocytes, affects gene expression in the mPFC. These findings suggest that further investigation into the potential role of astrocyte-mediated m6A methylation in the mPFC is warranted.

Berberine (BBN) is a naturally occurring alkaloid as a secondary metabolite in many plants and exhibits several benefits including neuroprotective activities. However, data on the neuromodulating potential of nanoformulated BBN are still lacking. In the present study, BBN loaded within iron oxide nanoparticles (BBN-IONP) were prepared and characterized by transmission electron microscopy FTIR, X-ray photoelectron spectroscopy particle-size distribution, zeta potential, and HPLC. The remyelinating neuroprotective potential of BBN-IONP relative to free BBN was evaluated against cuprizone (CPZ)-induced neurotoxicity (rats administered 0.2% CPZ powder (w/w) for five weeks). CPZ rats were treated with either free BBN or IONP-BBN (50 mg/kg/day, orally) for 14 days. Cognitive function was estimated using Y-maze. Biochemically, total antioxidant capacity lipid peroxides and reduced glutathione in the brain tissue, as well as, serum interferon-gamma levels were estimated. Moreover, the genetic expression contents of myelin basic protein Matrix metallopeptidase-9 Tumor necrosis factor-α (TNF-α), and S100β were measured. The histopathological patterns and immunohistochemical assessment of Glial Fibrillary Acidic Protein in both cerebral cortex and hippocampus CA1 regions were investigated. CPZ-rats treated with either free BBN or IONP-BBN demonstrated memory restoring, anti-oxidative, anti-inflammatory, anti-astrocytic, and remyelinating activities. Comparing free BBN with IONP-BBN revealed that the latter altered the neuromodulating activities of BBN, showing superior neuroprotective activities of IONP-BBN relative to BBN. In conclusion, both forms of BBN possess neuroprotective potential. However, the use of IONPs for brain delivery and the safety of these nano-based forms need further investigation.

Alzheimer's disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer's disease treatments in the last decades. However, existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic, necessitating the exploration of alternative therapeutic strategies. Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer's disease patients, with dysregulated astrocytic purinergic receptors, particularly the P2Y1 receptor, all of which constitute the pathophysiology of Alzheimer's disease. These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer's disease. This review delves into recent insights into the association between P2Y1 receptor and Alzheimer's disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer's disease by mitigating neuroinflammation, thus offering promising avenues for developing drugs for Alzheimer's disease and potentially contributing to the development of more effective treatments.

Nanoplastics, as environmental contaminants, are thought to have irreversible impacts on the developing brains of infants and early children; however, the degree of the effects and the mechanisms of damage are unknown. In this study, spatial transcriptomics was used to investigate changes in the hippocampal region of rats descended from maternal exposure to polystyrene nanoplastics (PS-NPs), and the transcriptomes of each spot were sequenced, allowing us to visualize the hippocampus's transcriptional landscape as well as clarify the gene expression profiles of each cell type. Spatial transcriptomics was used to explore changes in the hippocampus region of rats exposed to PS-NPs during brain formation and maturation.The study's findings showed that the offspring hippocampal region had fewer neurons, more astrocytes, and more excitatory neurons 1(ExN1). The pseudo-time study of astrocytes revealed a decrease in C3-type astrocytes and an increase in C2-type astrocytes. This finding raises the possibility that memory impairment in the offspring may result from the developmental obstruction of astrocytes following the intervention of PS-NPs. Moreover, the annotations of four hippocampus regions, CA1, CA2-3, DG, and HILUS, as well as the GO and GSVA of several cell types, revealed deficiencies that can contribute to learning memory impairment. The analysis suggested that decreased neuroglutamate (Glutamate) and γ-aminobutyric acid (GABA) secretion in offspring after PS-NPs intervention was associated with depression. Lastly, intercellular communication revealed alterations in several ligand receptor pathways associated with an increase in astrocytes. In conclusion, spatial transcriptomics reveals that maternal exposure to nanoplastics influences the development of the offspring's hippocampal brain and causes neurotoxicity, which accounts for the offspring's reduction in learning memory function.