CNS Neuroscience & Therapeutics最新文献

Objective: Histone deacetylases are implicated in ischemic stroke, yet the role of HDAC5 remains poorly defined. This study aimed to determine the pathological significance of HDAC5 after cerebral ischemia, clarify its involvement in post-ischemic NF-κB p65/NLRP3 signaling, and evaluate an HDAC5-targeted extracellular vesicle (EV)-based therapeutic strategy.

Methods: HDAC5 expression after ischemic injury was examined in a mouse middle cerebral artery occlusion (MCAO) model by western blotting and immunofluorescence. Its function was assessed by gain- and loss-of-function experiments in BV2 cells and MCAO mice. Infarct volume, cerebral blood flow, and neurological recovery were evaluated by TTC staining, magnetic resonance imaging (MRI), color Doppler imaging, and behavioral tests. Co-immunoprecipitation, acetylation analysis, and cytoplasmic/nuclear fractionation were used to explore the underlying mechanism. Human neural stem cell-derived EVs loaded with miR-9-5p and modified with RGD peptide were further tested as a targeted therapeutic approach.

Results: HDAC5 was markedly upregulated after MCAO, localizing mainly to neurons in the ischemic core and microglia in the penumbra, together with increased NLRP3 expression. In BV2 cells, HDAC5 overexpression increased NLRP3 expression, whereas HDAC5 knockdown reduced it. In vivo, AAV-mediated HDAC5 knockdown decreased NLRP3 levels, reduced infarct volume, improved blood flow recovery, and ameliorated motor deficits after MCAO. Mechanistically, HDAC5 interacted with NF-κB p65 rather than NLRP3. HDAC5 knockdown increased p65 acetylation and reduced its nuclear translocation, consistent with suppression of NLRP3-associated inflammatory signaling. Moreover, engineered RGD-EV:miR-9-5p was efficiently taken up by microglia, suppressed HDAC5 and NLRP3 expression, and improved histological and functional outcomes after MCAO.

Conclusion: These findings identify HDAC5 as a previously underappreciated regulator of post-ischemic inflammatory injury and support a role for the HDAC5/NF-κB p65/NLRP3 axis in cerebral ischemia. Engineered RGD-EV:miR-9-5p may therefore represent a promising targeted therapeutic strategy for ischemic stroke.

Aims: Epilepsy is a common neurological disorder, often presenting with psychiatric comorbidities and cognitive impairment. Neuroimaging studies have suggested associations between epilepsy and subcortical volumetric abnormalities. The genetic basis between epilepsy and subcortical volume abnormalities is, however, poorly understood, particularly if they share a common genetic architecture.

Methods: To investigate polygenic overlap, we employed the bivariate causal mixture model (MiXeR) to analyze genome-wide association data from various epilepsy subtypes (genetic generalized epilepsy [GGE]: n = 49,388, all epilepsy [EP]: n = 69,995, focal epilepsy: n = 57,375) and 16 subcortical volumetric phenotypes (n = 33,224). We identified shared genomic loci through conditional and conjunctional false discovery rate analyses (cond/conjFDR).

Results: MiXeR results suggest substantial shared genetic variants between subcortical volume and common epilepsies. ConjFDR analysis identified 33 distinct shared loci between GGE and subcortical volumetric phenotypes. The shared loci were mapped to 322 protein-coding genes. Among these, 49 genes showed significant expression-trait associations with both GGE and subcortical volume phenotypes, and 12 of the 322 genes were also associated with cognitive, mental health, and personality-related traits.

Conclusion: We dissected the shared genetic architecture between common epilepsies and subcortical volumes. Expression-trait association analyses further identified candidate genes associated with cognitive, mental health, and personality-related phenotypes.

Background: Adolescents with non-suicidal self-injury (NSSI) frequently exhibit severe sleep disturbances and heterogeneous cognitive impairments, yet the underlying neurophysiological basis remains unclear. The glymphatic system, a sleep-dependent macroscopic clearance network, is critical for metabolic waste removal and neurocognitive homeostasis. Therefore, this study aimed to investigate the physiological role of glymphatic function in linking sleep burden to distinct cognitive performances in adolescents with NSSI.

Methods: We assessed 44 NSSI adolescents and 33 healthy controls (HCs). Using resting-state functional magnetic resonance imaging (rs-fMRI), glymphatic function was quantified by calculating the coupling strength between global blood-oxygen-level-dependent (gBOLD) signals and cerebrospinal fluid (CSF) flow. To capture the heterogeneity in their cognitive profiles, we evaluated "hot" affective decision-making via the Iowa Gambling Task (IGT) and "cold" executive function via the Wisconsin Card Sorting Test (WCST). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI).

Results: In the NSSI group, poorer sleep quality was positively correlated with stronger gBOLD-CSF coupling (r = 0.317, p = 0.036), and stronger gBOLD-CSF coupling predicted better IGT performance, especially during the high-load strategy phase (Block 3) (r = 0.447, p = 0.002). Furthermore, glymphatic function fully mediated the relationship between sleep quality and affective decision-making performance (indirect effect = 0.682, 95% CI [0.062, 1.515]). Interaction analyses confirmed this physiological-behavioral coupling was disease-specific (present only in NSSI; interaction p = 0.011) and domain-specific (supporting "hot" affective cognition rather than "cold" executive function).

Conclusions: In NSSI adolescents, sleep-associated glymphatic upregulation reflects a stress-induced compensatory response. This mechanism domain-specifically preserves high-load affective decision-making against severe psychopathological stress. These findings highlight brain metabolic clearance as a novel physiological target for bolstering cognitive resilience in high-risk youth.

Background: Patients with chronic temporal lobe epilepsy (TLE) frequently experience various sleep disorders, characterized by reduced sleep duration, diminished sleep stages, and disrupted sleep patterns. Recent research has identified a population of GABAergic neurons in the ventral zona incerta (ZI) that is instrumental in promoting sleep, along with a neural pathway that connects the cerebellar dentate nucleus (CDN) to the ZI. However, the precise role of this circuit in regulating sleep patterns remains inadequately understood.

Methods: This study employed anatomical, chemogenetic, optogenetic, and immunofluorescence staining techniques to investigate the potential of the CDN-ZI circuit in ameliorating sleep disturbances associated with TLE.

Results: Our findings indicate that pilocarpine-treated mice exhibit significant sleep fragmentation and reduced sleep duration, particularly during non-rapid eye movement sleep. By employing optogenetic and chemogenetic methods to target CDN glutamatergic neurons, we observed a decrease in sleep fragmentation, an increase in overall sleep duration, and an enhancement in sleep quality in pilocarpine-treated mice. The inhibition of the CDN-ZI glutamatergic circuit through optogenetic and chemogenetic methods resulted in substantial improvements in sleep disturbances following TLE.

Conclusions: Targeting the CDN-ZI glutamatergic circuit represents a promising therapeutic strategy for addressing sleep disorders resulting from chronic TLE.

Objective: To investigate whether electroacupuncture (EA) at Zusanli (ST36) ameliorates alcohol-related cognitive impairment (ARCI) by restoring intestinal barrier integrity and to elucidate the role of the vagus nerve in this "gut-to-brain" protective mechanism.

Methods: An ARCI mouse model was established by daily ethanol gavage for 28 days. Mice received EA at ST36 from day 15 onwards. Behavioral tests (MWM, OFT, EPM) were conducted to assess cognitive and emotional function. Time-course analysis of intestinal pathology (H&E, ZO-1), permeability (FITC-LPS, DAO), and neuroinflammation (LPS, IBA-1, cytokines) was performed. The role of the vagus nerve was investigated using ipsilateral DMV lesion and exogenous LPS challenge.

Results: Chronic alcohol exposure caused significant cognitive deficits, anxiety-like behaviors, and body weight loss, accompanied by early-onset intestinal barrier disruption and elevated LPS, which preceded central neuroinflammation. EA at ST36 significantly ameliorated these behavioral and pathological changes. EA activated DMV cholinergic neurons, restored ZO-1 expression, and reduced LPS translocation. Crucially, both DMV lesion and exogenous LPS administration abolished EA's protective effects on the intestinal barrier, neuroinflammation, and behavior.

Conclusion: EA at ST36 alleviates ARCI by activating the vagus nerve to restore intestinal barrier integrity, thereby preventing gut-derived LPS from triggering neuroinflammation. This identifies a key vagal-dependent mechanism and supports EA as a promising intervention for ARCI.

Aims: This study aimed to evaluate the effects of dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, on brain microvascular endothelial cell (BMEC) function and blood-brain barrier (BBB) integrity in juvenile mice following traumatic brain injury (TBI). We specifically assessed the effects of DEX on ER stress, neuroinflammation, and ferroptosis and explored potential sex-specific responses.

Methods: Male and female juvenile mice were subjected to an impact-acceleration TBI model. DEX was administered during the acute phase post-injury. Muscle strength and sensorimotor coordination were measured, and BBB permeability was assessed. BMECs and cerebral microvessels were isolated from the injured and control regions for molecular analysis of inflammatory markers, ER stress activation, ferroptosis, and expression of tight junction markers.

Results: DEX treatment improved motor and coordination outcomes and reduced BBB leakage in both sexes after TBI. Molecular analyses revealed decreased inflammatory signaling, ER stress, and ferroptosis-related oxidative stress pathways in BMECs with DEX treatment. Importantly, DEX led to greater upregulation of selected tight junction markers in female mice than in male mice, suggesting possible sex-specific differences in α2-adrenergic receptor expression.

Conclusion: DEX provides both behavioral and cellular protection following juvenile TBI, with potential sex-dependent effects on BMECs and BBB function.