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Sleep plays an essential role in all studied animals with a nervous system. However, sleep deprivation leads to various pathological changes and neurobehavioral problems. Astrocytes are the most abundant cells in the brain and are involved in various important functions, including neurotransmitter and ion homeostasis, synaptic and neuronal modulation, and blood–brain barrier maintenance; furthermore, they are associated with numerous neurodegenerative diseases, pain, and mood disorders. Moreover, astrocytes are increasingly being recognized as vital contributors to the regulation of sleep-wake cycles, both locally and in specific neural circuits. In this review, we begin by describing the role of astrocytes in regulating sleep and circadian rhythms, focusing on: (i) neuronal activity; (ii) metabolism; (iii) the glymphatic system; (iv) neuroinflammation; and (v) astrocyte–microglia cross-talk. Moreover, we review the role of astrocytes in sleep deprivation comorbidities and sleep deprivation-related brain disorders. Finally, we discuss potential interventions targeting astrocytes to prevent or treat sleep deprivation-related brain disorders. Pursuing these questions would pave the way for a deeper understanding of the cellular and neural mechanisms underlying sleep deprivation-comorbid brain disorders.

Astrocytes, the most abundant cells in the brain, are integral to sleep regulation. In the context of a healthy neural environment, these glial cells exert a profound influence on the sleep-wake cycle, modulating both rapid eye movement (REM) and non-REM sleep phases. However, emerging literature underscores perturbations in astrocytic function as potential etiological factors in sleep disorders, either as protopathy or comorbidity. As known, sleep disorders significantly increase the risk of neurodegenerative, cardiovascular, metabolic, or psychiatric diseases. Meanwhile, sleep disorders are commonly screened as comorbidities in various neurodegenerative diseases, epilepsy, and others. Building on existing research that examines the role of astrocytes in sleep disorders, this review aims to elucidate the potential mechanisms by which astrocytes influence sleep regulation and contribute to sleep disorders in the varied settings of brain diseases. The review emphasizes the significance of astrocyte-mediated mechanisms in sleep disorders and their associated comorbidities, highlighting the need for further research.

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer’s diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.

Aims This study investigates whether trimethylamine N‐oxide (TMAO) mitigates perioperative neurocognitive disorders (PND) by modulating Annexin A1 (ANXA1) and microglial polarization, thereby reducing neuroinflammation in the hippocampus. Methods A murine PND model was established via tibial fracture surgery under sevoflurane anesthesia. Mice were pretreated with TMAO (1.2, 12, or 120 mg/kg) for 21 days. Cognitive function was assessed using Y‐maze and fear conditioning tests. Hippocampal ANXA1 expression, microglial polarization (M1/M2 phenotypes), and cytokine levels (TNF‐α, IL‐1β, TGF‐β) were analyzed. Results TMAO administration (12 mg/kg) significantly improved cognitive performance. Mechanistically, TMAO upregulated ANXA1 expression, facilitating its nuclear translocation in microglia and shifting their polarization from pro‐inflammatory M1 phenotype to anti‐inflammatory M2 phenotype. This transition consequently suppressed pro‐inflammatory cytokines (TNF‐α and IL‐1β) while elevating TGF‐β. Additionally, TMAO attenuated microglial activation and associated neuroinflammatory morphological alterations. Conclusion Physiological concentrations of TMAO confer neuroprotection by augmenting ANXA1‐mediated resolution of neuroinflammation, supporting its therapeutic potential for preventing PND. This schematic depicts the proposed mechanism by which TMAO alleviates PND by modulating neuroinflammation in the hippocampus. Anesthesia and surgery disrupt the balance between pro‐inflammatory (e.g., IL‐1β, TNF‐α) and anti‐inflammatory cytokines (e.g., TGF‐β), promoting M1 microglial polarization and cognitive impairment. TMAO pretreatment upregulates ANXA1, facilitating its nuclear translocation and shifting microglia toward the anti‐inflammatory M2 phenotype. This transition reduces pro‐inflammatory cytokines, suppresses microglial activation, and improves cognitive function. The diagram highlights key mediators (TMAO, ANXA1, TGF‐β) and cellular responses (microglial polarization, cytokine shifts) underlying TMAO's neuroprotective effects in PND.

Oxidative stress is believed to play critical pathophysiological roles in ischemic brain injury, and the nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling pathway is recognized as the most crucial endogenous antioxidant stress damage route. Some research have demonstrated that Nrf2 play critical roles in oxidative stress after ischemic stroke, but the underlying mechanism are not fully elucidated. This study reveals that Nrf2 is modified by SUMOylation and identifies Sentrin/SUMO‐specific protease 6 (SENP6) as a negative regulator of Nrf2 SUMOylation. Notably, SENP6 binds to and mediates the deSUMOylation of Nrf2, which in turn inhibits antioxidant response by enhancing ubiquitination‐dependent degradation of Nrf2, thereby reducing its transcriptional activity, inducing oxidative stress and aggravating neuronal apoptosis after ischemic stroke. Additionally, blocking the interaction between SENP6 and Nrf2 with a cell membrane‐permeable peptide (Tat‐Nrf2) preserves the SUMOylation of Nrf2, effectively attenuates oxidative stress, and rescues neurological functions in mice subjected to ischemic stroke. Furthermore, no toxicity is observed when high doses Tat‐Nrf2 are injected into nonischemic mice. Collectively, this study uncovers a previously unidentified mechanism whereby SUMOylation of Nrf2 regulates oxidative stress and strongly indicates that interventions targeting SENP6 or its interaction with Nrf2 may provide therapeutic benefits for ischemic stroke. This study uncovers a previously unrecognized role for SENP6‐mediated deSUMOylation of Nrf2 in neuronal oxidative stress after ischemic stroke. Mechanistically, SENP6 binds to and mediates deSUMOylation of Nrf2, which in turn inhibits the antioxidant response by enhancing ubiquitination‐dependent degradation of Nrf2, thereby inducing oxidative stress and exacerbating neuronal damage, highlighting the SENP6‐Nrf2 axis as a promising therapeutic target for ischemic stroke.