Antibiotics (AB) are widely abused in medicine and may be a risk factor for mental health. To better understand their effects, we observed mental disorder symptoms in AB-treated mice and patients, and investigated possible mechanisms. Using AB-treated mice, we found obvious anxiety-like behaviors, along with differential gut microbiota (mainly Firmicutes and Bacteroidota), reduced short-chain fatty acids (SCFAs), and disrupted gut-brain lipid metabolism. Acetylcholine decreased in feces, colon wall, serum, and hippocampus of AB-treated mice, and this reduction was significantly correlated with anxiety-like behaviors. Moreover, using AB-treated patients (n = 55), AB-naïve patients (n = 60), and healthy controls (n = 60), we also observed the obvious anxiety symptoms in AB-treated patients, along with differential gut microbiota (mainly Firmicutes), reduced SCFAs, and disrupted lipid metabolism in feces and serum. AB-treated patients showed consistently lower serum and fecal acetylcholine, which was highly correlated with anxiety symptoms. In both AB-treated mice and patients, co-occurrence analysis indicated that the "Bacteroides-acetylcholine" pair may play an important role in AB-induced anxiety. At the species levels, Bacteroides_caecimuris in AB-treated mice and Bacteroides_plebeius in AB-treated patients were both decreased and significantly correlated with acetylcholine. Furthermore, exogenous methacholine (an acetylcholine derivative) intervention effectively alleviated anxiety-like behaviors and suppressed hippocampal microglial activation in AB-treated mice. Together, our findings highlight the harmful effects of aggressive AB treatment on mood and show the potential of acetylcholine or its derivative to reverse this effect.
Postoperative delirium (POD) following cardiac surgery is a severe complication. There is evidence of a link between neuroinflammation and neurodegeneration in POD. We investigated the preoperative proinflammatory interleukin-6 (IL-6) and neuronal damage marker phosphorylated tau protein 181 (p-tau181) to POD while considering preoperative heart-brain axis related factors. The prospective FINd DElirium RIsk factors (FINDERI) is an observational study in patients undergoing cardiac surgery. Biomarkers IL-6 and p-tau181 were measured in blood samples. For statistics, we utilized multiple logistic regression analyses and advanced machine learning techniques. In 491 patients, 106 (21.6%) developed POD. The age of patients with POD was significantly higher than that of patients without POD (p < 0.001). Preoperative IL-6 and p-tau181 levels independently predicted POD [IL-6: area under the curve (AUC) = 0.605, p < 0.005; p-tau181: AUC = 0.641, p < 0.0001)]. A multiple logistic regression analysis of preoperative log-transformed biomarkers levels (p-tau181, IL-6), female sex and cognitive performance increased the AUC (0.710, p < 0.0001) in predicting POD. We created a decision tree prediction model including preoperative p-tau181, IL-6, and the severity of mitral valve disease (training data: AUC = 0.672, p < 0.0001; validation data: AUC = 0.642, p < 0.05). The LASSO regression showed an increased AUC in the training (0.751, p < 0.0001) and validation dataset (0.652, p < 0.05). Our results demonstrate that the combined assessment of preoperatively measured p-tau181 and IL-6, preoperative mitral valve disease, cognitive performance and female sex, significantly predicts POD. These findings provide evidence that neuroinflammation and neuronal cell damage are associated with POD.
Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor subtypes, including the serotonin 1B receptor (5-HT1BR). Given the known role of 5-HT1BR in mediating depressive phenotypes and promoting neural plasticity, we hypothesized that it mediates the effects of psilocybin on neural activity and behavior. We first examined the acute neural response to psilocybin in mice lacking 5-HT1BR. We found that 5-HT1BR expression influenced brain-wide activity following psilocybin administration, measured by differences in the patterns of the immediate early gene c-Fos, across regions involved in emotional processing and cognitive function, including the amygdala and other subcortical limbic structures. Functionally, we demonstrated that 5-HT1BR mediates some of the acute and persisting behavioral effects of psilocybin. Although there was no effect of 5-HT1BR expression on the acute head twitch response, mice lacking 5-HT1BRs had attenuated hypolocomotion to psilocybin. We also measured the persisting effects of psilocybin on anhedonia and anxiety-like behavior using transgenic and pharmacological 5-HT1BR loss-of-function models. Although there were effects of sex and stress paradigms, we found that 5-HT1B is involved in mediating some of the longer-lasting behavioral responses to psilocybin. Finally, using a network analysis, we identified neural circuits through which 5-H1BR may modulate the response to psilocybin. Our findings suggest that the 5-HT1BR influences brain-wide neural changes following psilocybin administration and may contribute to its enduring antidepressant-like effects in mice.
The transcranial alternating current stimulation (tACS) has been reported to improve attention-related neurophysiological measures in individuals with attention deficit hyperactivity disorder (ADHD); however, robust clinical evidence remains limited. This randomized, double-blind, sham-controlled trial aimed to explore the clinical efficacy, safety, and underlying neural mechanisms of tACS in adults with ADHD. A total of 56 adults with ADHD were randomly assigned in a 1:1 ratio to receive either active tACS or sham stimulation across 20 sessions over four consecutive weeks, with follow-up assessments conducted at week 8 and week 16. Clinical symptoms and resting-state magnetoencephalography (MEG) data were collected before and after the intervention. The tACS group showed significantly greater improvement in inattention symptoms compared to the sham group at week 4, as measured by the Adult ADHD Self-Report Scale - inattention subscale (ASRS-IA) (-10.1 vs. -5.5, p < 0.001, Cohen's d = 1.02). This improvement was sustained at week 8 but attenuated at week 16. Safety profiles were comparable between the two groups. Furthermore, the reduction in ASRS-IA scores was positively correlated with decreased gamma-band connectivity between the orbitofrontal cortex and the precuneus, indicating a desynchronization of neural activity in these brain regions. These findings suggest that tACS may serve as a promising neuromodulation intervention for adult ADHD, demonstrating both clinical benefits and specific neurophysiological mechanisms. TRIAL REGISTRATION: ChiCTR Identifier: ChiCTR2400081121.
Prenatal exposure to a heightened maternal immune response, such as that triggered by viral infection in the mother, can alter fetal brain development and increase risk of neurodevelopmental disorders in offspring, including autism (ASD) and schizophrenia. However, the cellular and molecular mechanisms linking early inflammatory signals to long-term changes in brain function remain unclear. While rodent models of maternal immune activation (MIA) display brain and behavioral disruptions, their translational relevance to humans is limited. To address this gap, we utilized a nonhuman primate (NHP) MIA model to examine how transient maternal immune responses in early gestation alter gene expression in the amygdala-a brain region essential for socioemotional behavior and implicated many neurodevelopmental disorders. Pregnant macaques were administered the viral mimic Poly(I:C) during the late first trimester, and amygdala samples were collected from 4-year-old male offspring for single-nucleus RNA sequencing (>71,000 nuclei). We identified 2768 unique differentially expressed genes (DEGs), concentrated in excitatory and inhibitory neurons of the lateral nucleus and microglia of the central nucleus. These DEGs converge on synaptic structure, neurotransmission, and neuroimmune signaling-core processes in circuit assembly and behavioral regulation. MIA-associated DEGs significantly overlap with high-confidence ASD- and psychosis-risk gene sets, directly linking prenatal immune events to human disease pathways. This study provides the first region- and cell-type-specific evidence in a primate model that transient prenatal maternal immune responses lead to lasting transcriptomic dysregulation. These findings reveal how early immune insults may alter neurodevelopment and offer a translational framework for identifying molecular targets for early intervention.
Migraine is a neurovascular disorder that poses a high burden to Veterans, who face a greater risk than sex-matched individuals in the general population. Genetic research on migraine in Veterans and its link to psychiatric comorbidities is limited. We present a meta-analysis of a genome-wide association study (GWAS) of migraine in a predominantly male sample of over 433,000 Veterans, including 87,859 cases, from the Million Veteran Program (MVP), identifying 49 genome-wide significant loci, with 36 novel to this study, of which 7 replicated in an independent prior GWAS (after Bonferroni correction for number of loci tested). Our analyses revealed 283 genes, including some newly associated with migraine: MAML3, CELF4, IRX1, ASXL1, SPOCD1, CXCL, and TLR4. In silico analyses showed enrichment in brain and uterine tissues, which may reflect broader hormonal or neuroendocrine pathways. Compared to previous migraine GWAS, our results show minimal vascular tissue enrichment, potentially reflecting the sample composition, which was predominantly men and Veterans. Migraine SNP-based heritability was 10% for men and 16% for women, and several sex-specific loci were identified through sex-stratified analyses. Despite high genetic correlations with neuropsychiatric disorders - including post-traumatic stress disorder, depression, and traumatic brain injury - Mendelian randomization analyses found no causal links. Finally, we prioritized potential migraine drug targets, including losmapimod (which reduces production of toxic DUX4 protein) and TLR4 antagonists.
Mental and substance use disorders profoundly affect global population health, while there is a notable absence of systematic studies focusing on their burden in the Chinese population. We estimated the burden of Global Burden of Diseases (GBD) 2021 for 10 mental disorders and two types of substance use disorders in China from 1990 to 2021. We presented the numbers and rates of prevalence, disability-adjusted life years (DALYs), years of life lost (YLL) and years lived with disability (YLDs), from national and 33 province-level administrative units in China. In 2021, China contributed 174.4 million prevalent cases (95% uncertainty interval [UI] 162.4-188.4 million) of mental disorders and 27.0 million prevalent cases (23.8-30.7 million) of substance use disorders. The age-standardized DALY rate for mental and substance disorders in China was lower than that in countries with high Socio-demographic Index (SDI) and middle SDI, as well as lower than global level. Depressive disorder and anxiety disorder being the two leading causes, accounting for 61.1% of mental disorder YLDs, and were most prevalent among individuals aged 15 and over. Population growth was an important contributor to the 62.0% increases in DALYs for mental disorder. Regionally, the age-standardized prevalence rates for mental disorders were higher in Eastern China, while substance use disorders were more prevalent in Western regions. These findings showed the burden of mental disorders in China has increased mainly due to the population growth and population aging. The comprehensive prevention and early intervention strategies is urgent to mitigate the burden and the impact for the public.
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