Chronic pain is increasingly recognized as a potential risk factor for cognitive decline, yet findings from observational studies are inconsistent. We conducted a meta-analysis to evaluate the long-term association between chronic pain and cognitive impairment. PubMed, Embase, and the Cochrane Library were searched from inception to January 2025 for longitudinal cohort studies assessing this relationship. Twenty-eight eligible cohorts comprising 7,914,407 participants were included. Adjusted odds ratios (ORs) were pooled using random-effects models; subgroup, sensitivity, and meta-regression analyses were performed to explore heterogeneity. Chronic pain was associated with a higher risk of cognitive impairment (pooled adjusted OR = 1.30; 95% CI: 1.14-1.47), an effect driven by dementia (pooled OR = 1.43; 95% CI: 1.23-1.65) rather than by global cognitive performance scores (pooled OR = 0.99; 95% CI: 0.88-1.11). Associations were stronger in studies with follow-up ≥5 years (OR = 1.37), in older populations (OR = 1.30), and in cohorts focusing on headache-related pain (OR = 1.42). Meta-regression indicated that depression was a key moderator of the association. These findings suggest that chronic pain is linked specifically to an increased risk of dementia, particularly among older individuals and those with headache-related pain. Integrative clinical strategies addressing pain and co-occurring depression, along with mechanistic and interventional studies using standardized cognitive endpoints, are warranted.

Chronic stress is a major risk factor for depression and disrupts myelin integrity in brain regions involved in emotional regulation. Although intermittent fasting (IF) improves metabolic and inflammatory states, its effects on stress-induced depression and demyelination remain unclear. Here, we investigated whether IF alleviates depression-like behaviors and myelin deficits in mice exposed to chronic restraint stress (CRS) and whether these effects involve modulation of the gut microbiota. Adult male C57BL/6 J mice underwent 14 days of CRS while maintained on either an ad libitum (AL) diet or an IF regimen. CRS induced robust depression-like phenotypes-characterized by increased immobility in the forced swimming test and reduced sucrose preference-without affecting locomotor activity, whereas IF significantly attenuated these behavioral abnormalities. Black-Gold II staining and myelin basic protein (MBP) immunofluorescence revealed marked demyelination in the corpus callosum, medial prefrontal cortex, and hippocampus of CRS mice, which was substantially reversed by IF. 16S rRNA sequencing demonstrated that IF reshaped gut microbial diversity and community composition under stress. Species-level analyses identified Prevotellamassilia timonensis and Muricoprocola aceti as positively associated with myelin integrity and behavioral improvement, whereas Anaeroplasma abactoclasticum showed negative associations. Functional pathway prediction further indicated that IF partially normalized stress-induced alterations in microbial metabolic functions. Collectively, these findings demonstrate that IF mitigates depression-like behaviors and preserves myelin integrity in CRS-exposed mice, potentially through gut microbiota-mediated mechanisms. IF may therefore represent a promising non-pharmacological strategy for alleviating stress-related neurobiological dysfunction.

Microglia-mediated neuroinflammation is increasingly recognized as a contributor to neurodegenerative disease progression. However, how microglia contribute to neuroinflammation-induced cognitive dysfunction remains unclear. Galectin-3 (Gal-3) is a microglia-enriched lectin that regulates inflammatory signaling and phagocytosis, a plausible mediator linking neuroinflammation to cognitive dysfunction. In a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation (0.5 mg/kg for 7 consecutive days), cognitive function was evaluated using the open field, Y-maze, and novel object recognition tests. In vivo CA1 extracellular electrophysiological recordings were used to analyze local field potentials (LFPs) and single-unit spiking activity. Dendritic morphology was evaluated by Golgi staining, and synaptic markers were quantified by immunofluorescence. In hippocampal CA1, microglia exhibited increased Gal-3 expression, enhanced phagocytic activity, and selectively increased engulfment of excitatory synapses. Systemic pharmacologic inhibition with TD139 and microglia-targeted Lgals3 knockdown (AAV-shLgals3 in Cx3cr1-CreERT2 mice) preserved excitatory synapses, restored CA1 gamma power, and improved cognitive performance in the neuroinflammation model. These results identify Gal-3-dependent microglial phagocytosis as a key mechanism linking neuroinflammation to cognitive dysfunction.

Background:Perioperative pain poses a significant challenge for surgical patients, with regional anesthesia commonly employed for postoperative pain relief. However, the utility of regional anesthesia is limited by the lack of real-time visualization during drug delivery and the rapid diffusion of anesthetics, which result in imprecise targeting and short duration of analgesia. Methods:An innovative ultrasound-guided drug sustained-release capsules were fabricated by bioinspired adhesive polylactic-co-glycolic acid (PLGA) loaded with ropivacaine microbubbles (APRMs). Ropivacaine release and ultrasonographic experiments of APRMs were conducted in vitro. For in vivo evaluation, a total of 127 adult male Sprague-Dawley rats (200-250 g) were used. Then, incision surgery and SNI-induced neuropathic pain were conducted for adult male rats to verify the ropivacaine release of APRMs in vivo. Ultrasound imaging was performed to confirm the ultrasonic visualization of APRMs. The in vivo fluorescence imaging experiment was conducted for the adhesion property of APRMs. Finally, systemic toxicity and tissue reaction were histologically evaluated. Results:APRMs achieved real-time visualization during drug delivery and significantly prolonged antinociceptive effects, maintaining mechanical analgesia for 9 days and thermal analgesia for up to 15 days, whereas free ropivacaine produced only transient effects (mechanical: approximately 24 h; thermal: approximately 4 h). Histological assessments revealed no toxicity or adverse tissue reactions, underscoring the safety of APRMs. Conclusion:APRMs represent a novel and promising strategy for pain management by integrating sustained anesthetic release, bioinspired adhesive properties for prolonged retention, and contrast-enhanced ultrasonography (CEUS) for real-time visualization. While these findings are encouraging, further in vivo validation and extended preclinical studies will be essential to confirm safety and efficacy before considering translation into clinical practice.

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but its clinical use is limited by serious gastrointestinal and respiratory adverse effects, including constipation, ileus, and pneumonia. The mechanisms linking these complications remain poorly understood. We tested the hypothesis that clozapine disrupts the gut-lung microbiota axis and that this disruption contributes to systemic toxicity. Adult male and female C57BL/6J mice received oral clozapine (5 mg/kg/day) or vehicle for 14 days. Clozapine significantly reduced body weight and fecal output, indicating gastrointestinal hypomotility. 16S rRNA sequencing revealed region-specific and sex-dependent alterations in microbial communities across the lungs, small intestine, cecum, and colon. Untargeted plasma metabolomics identified systemic metabolic changes in both sexes, including increased D-pyroglutamic acid and glutathione, consistent with oxidative and metabolic stress. Correlation analyses demonstrated coordinated associations among reduced fecal output, altered intestinal taxa, and circulating metabolites, indicating disruption of an integrated microbiota-metabolite network. Functionally, clozapine pretreatment significantly decreased survival following lipopolysaccharide-induced acute lung injury, indicating increased pulmonary vulnerability. Together, these findings suggest that clozapine disrupts the gut-lung microbiota-metabolite axis, linking gastrointestinal hypomotility with heightened respiratory susceptibility. This microbiota-centered framework provides mechanistic insight into clozapine-associated systemic toxicity and highlights microbiota-targeted strategies as potential approaches to improve the safety of clozapine therapy in treatment-resistant schizophrenia.

Xanomeline-trospium is a first-in-class muscarinic receptor-based antipsychotic that improves schizophrenia symptoms without dopamine D2 receptor antagonism. Although gastrointestinal (GI) adverse effects have been reported, its broader effects on host microbiota and susceptibility to respiratory injury remain unclear. We investigated the effects of xanomeline and xanomeline-trospium on gut and lung microbiota, host metabolism, and outcomes in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in male and female mice. Adult mice received vehicle, xanomeline, or xanomeline-trospium for 15 days. Body weight was monitored longitudinally, fecal output was measured, gut and lung microbiota were profiled using 16S rRNA sequencing, and untargeted serum metabolomics was performed using UPLC-QTOF/MS. ALI was induced by intratracheal LPS administration, and survival was assessed for seven days. Xanomeline induced weight loss in female mice and constipation in both sexes, and these effects were attenuated by trospium co-administration. Xanomeline-trospium was associated with sex- and region-associated alterations in gut microbiota, with greater remodeling in the cecum and colon, and also altered lung microbiota composition in both sexes. Integrated multi-omics analyses revealed sex-associated links among specific bacterial taxa, circulating metabolites, and host phenotypes. In the ALI model, xanomeline-trospium significantly increased LPS-induced mortality in female mice but not in male mice; however, formal interaction analysis did not support a significant sex-dependent treatment effect. These findings suggest that xanomeline-trospium alters gut-lung microbiota and host metabolic networks and may influence respiratory vulnerability.

Postoperative pain and opioid-related adverse effects remain significant concerns in pediatric surgical patients. Esketamine, an NMDA receptor antagonist, may enhance analgesia and reduce opioid consumption at low doses. This study aimed to evaluate the effects of low-dose esketamine combined with hydromorphone for PCIA on postoperative pain control, bowel recovery, and safety in children undergoing abdominal surgery. This randomized controlled clinical trial enrolled children aged from 3 to 12 years, who were scheduled to undergo abdominal surgery under general anesthesia and consented to the use of a PCIA pump. The study compared two groups. In the EH group (n = 49), esketamine (10 μg/kg/h) and hydromorphone (1 μg/kg/h), with bolus doses of hydromorphone 2 μg/kg and esketamine 20 μg/kg. In the H group (n = 49), analgesia was provided solely with hydromorphone (2 μg/kg/h), with bolus doses of 4 μg/kg. An identical lockout interval of 20 min was used. The primary outcome measured was the time-weighted average (TWA) pain score in the first 24 h postoperatively. Key secondary outcomes included the cumulative hydromorphone consumption within 48 h, the incidence of adverse events within 48 h, the time to first defecation, and the length of postoperative hospital stay. In comparison to the H group, the EH group demonstrated a significantly lower movement TWA pain score in the first 24 h postoperatively (1.90 vs 3.67; mean difference (MD), 1.23; 95

INTRODUCTION:Transcranial alternating current stimulation (tACS), which can noninvasively entrain oscillatory brain activity, has attracted scientific attention as a possible technique to control pain. However, there is a scarcity of studies investigating the preventive effect of tACS on postoperative pain. METHODS:This double-blind, randomized, sham-controlled trial enrolled 72 patients undergoing elective video-assisted thoracoscopic surgery (VATS). Patients were randomly allocated (1:1) to receive a single 20-min session of α-tACS on the primary somatosensory cortex (S1) or sham stimulation postoperatively. The primary outcomes were postoperative numerical rating scale pain scores and opioid consumption at 24 h postoperatively. Secondary outcomes included cumulative opioid consumption within 48 h and Quality of Recovery-15 (QoR-15) score. Adverse events were also assessed. RESULTS:The tACS group exhibited significantly lower resting pain scores versus the sham group (β = -0.49, 95% confidence interval [CI], -0.78 to -0.20, p = 0.001) and lower movement pain scores versus the sham group (β = -0.45, 95% CI, -0.84 to -0.06, p = 0.025), though cumulative opioid consumption showed no difference at 24 h (median difference [MD] = 1.0 mg; 95% CI, -2.3 to 2.5; p = 0.76) and 48 h (MD = 3.3 mg; 95% CI, -0.6 to 9.1; p = 0.10) postoperatively. Additionally, the area under the curve for resting pain over 2-24 h (AUC2-24 h) and 2-48 h (AUC2-48 h), as well as the AUC2-48 h of movement pain scores, were significantly lower in the tACS group. Moreover, QoR-15 scores and adverse events were also comparable. CONCLUSION:For patients undergoing VATS, a single α-tACS treatment targeting the bilateral S1 regions yielded a statistically significant yet modest reduction in postoperative pain. However, no significant decrease in postoperative opioid consumption was observed, and further research is warranted. TRIAL REGISTRATION:Chinese Registry of Clinical Trials: ChiCTR2300078723.

Major depressive disorder (MDD) is a leading cause of disability worldwide, and currently available antidepressants remain limited by delayed onset of action, incomplete response, and adverse effects. Ketamine is a rapid-acting antidepressant, whereas xanomeline, an M1/M4 muscarinic receptor agonist, may represent a mechanistically distinct non-monoaminergic strategy. However, the molecular basis by which xanomeline may influence depression-related pathways, and its relationship to ketamine, remain unclear. We used network pharmacology and molecular docking to compare the shared and distinct molecular mechanisms of xanomeline and ketamine in MDD. Potential drug targets were collected from public databases and intersected with MDD-related targets. Protein-protein interaction analysis was performed to identify hub genes, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Drug-pathway-target-disease networks were constructed, and shared core targets were further evaluated by molecular docking. We identified 368 overlapping targets for xanomeline-MDD and 714 for ketamine-MDD. Three KEGG pathways were shared between the two networks: EGFR tyrosine kinase inhibitor resistance, Ras signaling, and Rap1 signaling. EGFR, insulin-like growth factor 1 receptor (IGF1R), and SRC proto-oncogene, non-receptor tyrosine kinase, emerged as common core targets. Xanomeline was more strongly associated with receptor tyrosine kinase and PI3K/AKT-related signaling, whereas ketamine was more strongly linked to synaptic transmission, NMDA receptor-related functions, and glutamatergic signaling. Molecular docking supported structurally plausible binding of both drugs to EGFR, IGF1R, and SRC. These findings suggest partial convergence on downstream plasticity-related signaling nodes despite distinct upstream mechanisms and warrant further experimental investigation. However, the results should be interpreted as hypothesis-generating rather than as evidence of shared functional target engagement.

BACKGROUND:Constipation is a prevalent functional gastrointestinal disorder that impairs quality of life and is frequently accompanied by psychological distress. Emerging evidence suggests a potential association between constipation and depression, possibly mediated by gut-brain axis dysfunction; however, epidemiological findings remain inconsistent. METHODS:We conducted a systematic review and meta-analysis of observational studies examining the association between constipation and depression in the general population. PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to October 1, 2025. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity, prediction intervals, subgroup analyses, sensitivity analyses, and publication bias were assessed. RESULTS:Eighteen studies involving 730,263 participants were included. Constipation was significantly associated with an increased risk of depression (OR = 2.08, 95% CI: 1.84-2.34), with substantial heterogeneity (I² = 92.6%). The association remained robust across sensitivity analyses. Stronger associations were observed in adolescents, in studies conducted in Asia and North America, in smaller studies, and in those using self-reported depression measures. Prediction interval analyses indicated a consistently positive association across diverse populations. CONCLUSIONS:This meta-analysis provides robust evidence that constipation is associated with a significantly increased risk of depression. These findings highlight the importance of integrated gastrointestinal and mental health care, particularly for younger individuals with chronic constipation, and support further prospective and mechanistic studies targeting the gut-brain axis.

Background:Multimorbidity is associated with adverse outcomes among older adult surgical patients, yet its role in postoperative delirium (POD) remains unclear. In the present study, we hypothesized that distinct pattern of multimorbidity is associated with increased incidence of POD. Methods:From January 2024 to December 2024, 819 older adult patients were recruited at the Second Affiliated Hospital of Nanjing Medical University. Latent class analysis was used to identify patient subgroups based on disease composition. Mediation effect analysis explored the relationship between subgroups, Edmonton frail scale (EFS), and cognitive performance. Multinomial logistic regression model was employed to predict the subgroup to which patients with different diseases belong. Results:Three clinically distinct multimorbidity subgroups were identified. Significant differences in EFS, mini-mental state examination (MMSE), and POD were observed among subgroups (p < 0.05). After adjustment for age and MMSE, we found that subgroup 2 mediated the occurrence of POD through frailty [Indirect effect = 0.043; (95%CI = 0.019 ~ 0.070)]. Multinomial logistic regression model demonstrated good predictive power for subgroups, with AUROC scores as follows: subgroup 1 = 0.993, subgroup 2 = 0.977, and subgroup 3 = 0.990. The AUPRC scores were also strong, with subgroup 1 = 0.995, subgroup 2 = 0.886, and subgroup 3 = 0.974. Conclusion:We identified a specific pattern of multimorbidities significantly associated with frailty, cognitive impairment, and POD risk. The high-risk subgroup's effect on POD was partially mediated by frailty. Multinomial logistic regression model accurately predicted subgroup membership, offering a potential tool for preoperative risk stratification.

Radial artery puncture, a routine arterial cannulation procedure for perioperative and critical care settings, is limited by high first-attempt failure and hematoma risk under experience-based practice. We aim to develop artificial intelligence (AI) - powered precise puncture guidance to reduce procedure-related complications and improve patient experience. In this study, Synthetic Data Vault (SDV) algorithm is used to generate patient data as training set data according to the real data provided by Biostudies. Ten machine learning models were built via Python, and performance was evaluated using accuracy, precision, recall and area under the receiver operating characteristic curve (AUC). In the real-world test cohort, there were 185 positive cases of the first-attempt radial artery puncture success, corresponding to a positive proportion of 72.27%. For the postoperative hematoma outcome, 40 positive cases were identified, with a positive proportion of 15.63%. Local Interpretable Model-agnostic Explanations (LIME) integrated with decision tree classifier identified the top 3 predictors of puncture-related adverse events, enabling individualized risk stratification for clinical decision-making. For first-attempt puncture success prediction in the test set, all models except logistic regression, Gaussian Naive Bayes (GNB) and k-Nearest Neighbors (KNN) achieved accuracy > 0.750; all except KNN and Light Gradient Boosting Machine (LGBM) had precision > 0.830. LGBM (0.951) and CatBoost (0.881) yielded the highest recall, while CatBoost (0.763) and eXtreme Gradient Boosting (XGB) (0.750) had the highest AUC. For post-puncture hematoma prediction, all models except KNN had accuracy > 0.840; the top three precision values were from Multilayer Perceptron Classifier (MLPC, 0.857), Linear Support Vector Classification (LinearSVC, 0.667) and Adaptive Boosting (ADAB, 0.556). GNB achieved the highest recall (0.450), and all models except decision tree and KNN had AUC > 0.750. XGB achieved the optimal overall performance for first-attempt radial artery puncture success prediction in the tested single-center cohort, while MLPC yielded the highest precision for post-puncture hematoma prediction among the 10 evaluated algorithms.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in multimodal pain management under the concept of enhanced recovery after surgery (ERAS), adverse reactions and safety events caused by their unreasonable use have become increasingly prominent. Drawing on the latest literature and evidence-based medicine domestically and abroad, and based on the research and practice frontiers of domestic perioperative analgesia, this working group has reached a consensus on several key domain—including the application regimens of NSAIDs for perioperative analgesia, drug interactions, and precautions as well as prevention strategies in special populations—yielding 12 definitive recommendations. This consensus aims to provide guidance for the standardized selection and application of NSAIDs for perioperative analgesia, and to further promote the rational, safe, and effective use of NSAIDs.

Microglial pyroptosis-mediated neuroinflammation emerges as a critical pathogenic mechanism underlying sepsis-associated encephalopathy (SAE). Epigenetic modifications, especially histone acetylation states, exert fundamental regulatory effects on microglial pyroptosis. Among these, histone deacetylase 3 (HDAC3) has been identified as a central epigenetic regulator orchestrating these processes. This study investigates the functional role of HDAC3 in microglial pyroptosis and its underlying mechanisms contributing to SAE-related cognitive impairment. To explore this, male C57BL/6 mice subjected to cecal ligation and puncture (CLP) served as the SAE model. We employed RGFP966, a selective HDAC3 inhibitor, administered at 20 mg/kg/day via daily subcutaneous injections for 14 days starting 2 h prior to CLP surgery. To specifically examine HDAC3’s role in microglia, we bilaterally injected recombinant adeno-associated virus (rAAV)-expressing rEGFP under the control of a DIO promoter into the hippocampus of Cx3cr1-Cre mice to achieve selective overexpression. Our data demonstrate that HDAC3 in microglia activates pyroptosis through the STING/NLRP3 pathway, exacerbating oxidative stress responses and impairing neural activity, ultimately leading to cognitive deficits in SAE. Furthermore, HDAC3 overexpression in microglia recapitulates these pathological changes, underscoring its central role in driving disease progression. Conversely, RGFP966 treatment effectively attenuates these abnormalities by suppressing HDAC3 expression and downstream inflammatory pathways. These findings highlight the therapeutic potential of targeting microglial HDAC3 to mitigate neuroinflammation and cognitive dysfunction in SAE, offering a novel direction for future clinical applications.

Chronic sleep deprivation (CSD) can induce cognitive impairment, but its molecular mechanism remains unclear. In this study, initial m⁶A RNA sequencing of the hippocampal CA3 region in CSD rats, coupled with differential gene expression analysis of the total RNA fraction, revealed downregulation of METTL3, which was consistent with impaired performance in the Morris Water Maze (MWM) and confirmed by qRT-PCR and Western blot. Further investigation showed that, in HT-22 cells, METTL3 knockdown exacerbated rapamycin-induced apoptosis. RNA sequencing of METTL3-knockdown cells identified gene modules and specific differentially expressed genes associated with METTL3 loss. Differential expression analysis revealed that CDKN1A was significantly upregulated following METTL3 knockdown. Methylated RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) further showed that METTL3 knockdown reduced the m⁶A methylation level of CDKN1A mRNA. In vivo, METTL3 overexpression in CSD rats reduced CDKN1A levels, decreased neuronal apoptosis, improved spatial memory, and alleviated CA3 neuronal damage. In vitro, METTL3 knockdown upregulated CDKN1A and promoted apoptosis in HT-22 cells, while CDKN1A knockdown reversed this effect. Collectively, our results demonstrate that METTL3 downregulation promotes CSD-induced cognitive impairment by driving CDKN1A-dependent neuronal apoptosis, thereby identifying the METTL3/CDKN1A axis as a potential therapeutic target.

Older patients are at an increased risk of developing hypotension following the induction of general anesthesia, which is linked to a higher incidence of postoperative complications, mortality, and morbidity. This study aimed to investigate the effectiveness of carotid velocity time integral variation (ΔcVTI) combined with the passive leg raising test (PLR) in predicting hypotension after anesthesia induction in elderly patients. This prospective observational study enrolled 75 older patients (65–75 years, ASA II–III) undergoing elective surgery under general anesthesia. Carotid blood flow was continuously monitored using a wearable Doppler ultrasound patch, and ΔcVTI (

Cognitive impairment in schizophrenia remains largely unaddressed by dopamine-based antipsychotics. Xanomeline-trospium (KarXT; Cobenfy®), a combination of the muscarinic M1/M4 receptor agonist xanomeline and the peripherally restricted antagonist trospium, effectively reduces psychosis but is associated with gastrointestinal adverse effects. Here, we tested whether KarXT reverses phencyclidine (PCP)-induced cognitive deficits through microbiota-associated mechanisms in adult male mice. Mice received saline or PCP (10 mg/kg/day, s.c.) on days 1-5 and 8-12, followed by vehicle or KarXT [xanomeline 2 mg/kg/day + trospium 1 mg/kg/day, intragastric] on days 15-28. Recognition memory was evaluated using the novel object recognition test (NORT), and lung and intestinal microbiota (small intestine, cecum, and colon) were profiled by 16S rRNA sequencing. KarXT significantly rescued PCP-induced recognition-memory deficits without exacerbating PCP-related reductions in weight gain or fecal output. Microbiome analyses revealed region-specific dysbiosis after PCP exposure, most pronounced in the small intestine and cecum. Several taxa elevated by PCP-including Bacteroides fragilis, Veillonella ratti, Megamonas funiformis, Cupriavidus numazuensis, and Acetanaerobacterium elongatum-were normalized following KarXT treatment. Notably, restoration of multiple pulmonary, cecal, and colonic taxa correlated positively with the NORT recognition index. These findings demonstrate that KarXT reverses PCP-induced cognitive dysfunction while modulating microbial composition in a region-specific manner. Elucidating these relationships may help optimize cognitive efficacy and reduce gastrointestinal adverse effects of muscarinic therapies for schizophrenia.

Demyelination and impaired remyelination are hallmark features of many neurodegenerative and psychiatric disorders. Although central mechanisms have been widely investigated, the contribution of peripheral immune organs such as the spleen remains poorly understood. In this study, we examined the role of the spleen and transforming growth factor-β1 (TGF-β1) in cuprizone (CPZ)-induced demyelination and remyelination in mice. Splenectomy performed before CPZ exposure significantly worsened demyelination in the corpus callosum, as indicated by reduced myelinated area and myelin basic protein (MBP) intensity. Likewise, splenectomy immediately after CPZ withdrawal markedly impaired remyelination during the recovery phase. Immunohistochemical analysis showed that splenectomy reduced TGF-β1 expression in the corpus callosum at both 2 and 7 weeks after surgery. Moreover, systemic administration of a neutralizing anti-TGF-β1 antibody during either the demyelination or remyelination phase reproduced the effects of splenectomy, resulting in greater myelin loss or reduced myelin repair, respectively. Antibody treatment significantly decreased TGF-β1 levels in both brain and plasma, which were positively correlated with the degree of myelination. Together, these findings reveal a previously unrecognized role of the spleen in preserving myelin integrity and facilitating repair through TGF-β1 signaling. They further suggest that the spleen-brain axis contributes to myelin homeostasis and that peripheral TGF-β1 may represent a potential biomarker and therapeutic target for demyelinating disorders.

The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups-NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)-and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral-central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum-CSF GFAP correlation was found in the BC group (r = 0.446, P = 0.033), which became markedly stronger in the BMCI group (r = 0.753, P < 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, P < 0.001), IL-4 (r = 0.412, P = 0.003), IL-6 (r = 0.296, P = 0.035), and TNF-α (r = 0.352, P = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum-CSF IL-6 correlation reached significance (r = 0.469, P = 0.024). These findings suggest that BBB disruption markedly enhances peripheral-central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.

Critical dynamics are thought to support optimal information processing in the brain. Although disrupted criticality has been implicated in various neuropsychiatric and neurodegenerative disorders, whether neuroinflammation impairs cognition by disrupting brain criticality remains unclear. Here, we investigated how neuroinflammation alters hippocampal CA1 network criticality and whether this disruption contributes to cognitive impairments. Using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation, we combined in vivo electrophysiology, behavioral assays, morphological analysis, and molecular interventions to investigate the effects of neuroinflammation on hippocampal network dynamics and cognitive function. We found that LPS-induced neuroinflammation reduced the excitability of excitatory neurons and weakened functional connectivity, accompanied by enhanced microglial pruning of excitatory synapses, dendritic spine loss, and AMPA receptor endocytosis. These structural and cellular alterations were associated with a shift of CA1 network dynamics toward a subcritical state, as indicated by an increased deviation from the criticality coefficient, and this network disruption was accompanied by impairments in working and recognition memory. To determine whether these alterations contribute to disrupted criticality and cognitive impairments, we selectively manipulated neuronal excitability and inter-neuronal interactions. Chemogenetic activation of CaMKII-positive neurons restored neuronal excitability, rescued network criticality, and improved cognitive performance. Likewise, inhibition of AMPA receptor endocytosis with the TAT-GluA23Y peptide restored inter-neuronal connectivity, and rescued both network criticality and cognitive function. Together, these findings support that neuroinflammation-driven synaptic alterations impair cognition, at least in part, by disrupting hippocampal criticality.