Brain, Behavior, and Immunity最新文献

Δ⁹-tetrahydrocannabinol (THC) has been studied for its neuroprotective benefits in disease and its ability to improve HIV-1-related symptoms in clinical and preclinical models. Chronic THC administration may cause reduced sensitivity to antinociceptive, hypothermic, and anxiolytic effects following acute THC administration, and HIV status may further influence these effects. Thus, the present study investigated the effects of an acute THC challenge after chronic THC exposure on behavioral and neuroinflammatory measures using the HIV-1 Tg26 neuroHIV mouse model. HIV-1 Tg26 transgenic [Tg26(+/-), n = 32(16f)] mice and their control littermates [Tg26(-/-), n = 31(16f)] received subcutaneous injections of vehicle solution or THC (3 mg/kg), once a day, 5 days per week, for 90 days. After a 7-day drug-free period, all mice were given a high dose of THC (10 mg/kg; intraperitoneally), and their body temperature, antinociception, locomotor activity, and elevated plus maze data were collected. To assess inflammation, cytokine/chemokine levels were assessed via Bio-Plex, and microglial quantification and microglial CCL3/MIP-1α were assessed via immunohistochemistry in various brain regions. THC metabolite levels in the plasma were also collected. A chronic THC history resulted in minor behavioral/physiological changes (e.g., increase in body temperature but no effects on antinociception or locomotor activity) but overall decreases in proinflammatory and anti-inflammatory cytokines/chemokines in various brain regions of female mice. Importantly, across behavioral measures, a chronic THC history attenuated the efficacy of the acute high THC challenge dose, resulting in reduced THC-induced hypothermia, antinociception, and hypolocomotion, especially in females, and occasionally in a genotype-dependent manner. In the elevated plus maze, the acute THC challenge increased anxiety-like behavior in female mice with a chronic THC history compared to chronic vehicle history females, whereas no effects were noted in males. Further, regardless of microglial quantity, Tg26(+/-) mice showed high microglial-CCL3/MIP-1α co-occurrence in a sex- and brain-region dependent manner (e.g., BLNa in females & DS in males). The data suggest that female mice may develop reduced sensitivity to THC's hypothermic, antinociceptive, and anxiolytic effects, and that this insensitivity development may depend on HIV genotype. The sex and genotype effects seen in the behavioral assays may be elucidated by differential effects in the inflammatory measures.

Background: Adverse childhood experiences (ACEs) are associated with poor health outcomes in adulthood including obesity, psychiatric symptoms, and elevated levels of inflammatory markers. Our previous work found ACEs are associated with altered gut microbiota composition. In the present work, we examined ACE associations with gut microbiota and peripheral measures of inflammation in pregnant women with or without obesity, and explored potential modifying factors including diet and depressive symptoms.

Methods: Female participants were recruited in the third trimester of pregnancy as part of a larger growth study of African-American infants. Participants were categorized as healthy weight (BMI < 25) or obese (BMI ≥ 30) based on their early pregnancy BMI. They completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and Center for Epidemiologic Studies Depression Scale (CES-D). Stool samples, blood, and dietary data were collected in the third trimester. Shotgun metagenomic sequencing was performed on DNA isolated from stool. Statistical models assessed relationships between gut microbiota and ACE. A false discovery rate (fdr) adjusted p-value q < 0.1 was considered statistically significant.

Results: 107 women completed questionnaires and provided stool in the third trimester. ACEs were positively associated with BMI and depressive symptom severity but not with gut microbiota composition. Depressive symptoms were significantly negatively associated with abundance of gut Bifidobacterium longum (q = 0.02) and positively associated with Bacteroides thetaiotaomicron (q = 0.02). Path analysis revealed that ACEs predicted pre-pregnancy BMI which predicted elevated inflammatory markers. ACEs also predicted more severe depressive symptoms in pregnancy, which was associated with gut microbiome composition. Finally, ACEs interacted with dietary intake of sugar and whole grains to impact markers of inflammation, the gut microbiome, and enzymes produced by gut microbiota.

Discussion: ACEs led to two risk pathways in pregnancy: one in which high pre-pregnancy BMI was linked with high levels of serum inflammatory markers during pregnancy, and the other in which greater depressive symptom severity was associated with alterations to the gut microbiome. Further, data suggested ACEs may influence the metabolic potential of the gut microbiome.

HIV-1-associated neurocognitive disorder (HAND) persists in over 40% of people with HIV despite effective antiretroviral therapy, underscoring the absence of targeted interventions. Disruption of the blood-brain barrier (BBB) is a hallmark of HAND, yet the mechanisms that link viral proteins to endothelial injury remain insufficiently understood. This study demonstrates that the HIV-1 envelope glycoprotein gp120 induces pyroptosis of brain microvascular endothelial cells (BMECs), thereby compromising BBB integrity. This process is mediated by the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent activation of the ROS/NF-κB/NLRP3 inflammasome axis. Unexpectedly, α7nAChR, typically regarded as anti-inflammatory, exhibits a paradoxical pathogenic role under HIV-1 gp120 exposure, driving inflammatory endothelial cell death rather than protection. Importantly, this detrimental pathway is effectively inhibited by two clinically approved drugs, memantine and metformin, through suppression of α7nAChR. These findings uncover endothelial pyroptosis as a previously unrecognized mechanism of gp120-induced BBB disruption, redefine the functional role of α7nAChR in HAND pathogenesis, and highlight a promising therapeutic strategy through drug repurposing. By revealing a targetable pathway with direct clinical applicability, this work provides mechanistic insights and translational opportunities for preserving BBB function in HIV-associated neuropathology.

Cognitive deficits, a characteristic feature of neuropsychiatric disorders, reflect perturbed activity in neuronal networks. Increasing evidence has linked neuroinflammation to impaired neuronal activity and resulting cognitive dysfunction, yet the underlying cellular mechanisms and developmental dynamics remain largely unclear. Here, we address this knowledge gap by investigating the Df(16)A mouse model of human 22q11.2 microdeletions, a prevalent chromosomal abnormality associated with an increased incidence of neuropsychiatric disorders. During early postnatal development, Df(16)A^+/- mice show an imbalance of inflammatory signaling markers accompanied by increased microglial density in the superficial layers of the prefrontal cortex. Consequently, spine densities of pyramidal neurons were decreased, resulting in disrupted patterns of prefrontal neuronal activity during development and poor performance in a set-shifting task at juvenile age. Early treatment with minocycline, an anti-inflammatory drug, lastingly rescued these deficits in Df(16)A^+/- mice, rebalancing signaling cascades and restoring neural activity as well as cognitive performance. These findings identify the early rebalancing of inflammatory signaling cascades as a promising therapeutic strategy for mitigating pathophysiological trajectories associated with the 22q11.2 deletion syndrome.

Background and objectives: Low-grade systemic inflammation contributes to the pathophysiology of severe mental illness (SMI) in a substantial subset of patients, who often experience greater disease burden and poorer treatment response. Elevated C-reactive protein (CRP), defined as CRP ≥ 3 mg/L, has been proposed to identify this group, but its non-specificity limits the biomarker's ability to guide targeted intervention. We aimed to determine the most consistent drivers of high CRP across bipolar disorder (BD), schizophrenia (SZ) and major depressive disorder (MDD), and to translate these into clinically actionable intervention targets using robust data-driven methods.

Methods: We pooled and harmonised data from three large French national SMI cohorts (n = 7149: 4797 bipolar disorder, 1958 schizophrenia and 394 resistant major depression) and classified participants by CRP ≥ 3 mg/L, as well as an alternative cut-off of 5 mg/L. We applied penalised logistic regression (PLR), random forests (RF) and unsupervised clustering, using 28 biopsychosocial variables to identify robust drivers of high-CRP status. We then grouped these into actionable targets and assessed relative dominance.

Results: In total, 30.16% of participants had CRP ≥ 3 mg/L. PLR identified female sex (OR [95% CI]: 1.60 [1.27, 1.93]), higher BMI (OR: 1.09 [1.07, 1.13]), current nicotine dependence (OR: 1.05 [1.02, 1.09]), lower HDL cholesterol (OR: 0.57 [0.44, 0.73]) and smoking (ex-smoker status OR: 0.84 [0.66, 0.98]) as consistent drivers. RF highlighted a similar set of key drivers, also including waist circumference, triglycerides and cardiovascular comorbidities. Clustering of the high-CRP group was almost entirely driven by smoking status and nicotine dependence. When grouped into actionable targets, the identified drivers accounted for 16% of variance in CRP status, with obesity emerging as most dominant contributor. This pattern was most pronounced in females; in males it was more diffuse, with a more prominent role for smoking.

Conclusions: We propose a decision tree framework where CRP can serve as a first-line screening marker for inflammation in SMI, with subsequent steps focusing on the main contributing factors to guide targeted interventions. Priority should be given to targeting obesity and metabolic dysregulation. Among females, hyperuricemia represents the next most appropriate target, whereas in males, smoking warrants greater attention. This stepwise approach provides a route from a non-specific biomarker to targeted treatment strategies and should be validated in prospective studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a multifactorial and incompletely understood etiology. Identifying exposures associated with reduced AD risk may help generate mechanistic hypotheses and inform future prevention strategies. To investigate such associations, we analyzed electronic health records from a national Israeli health provider, retrospectively comparing 9124 individuals with AD to 18,248 matched controls. We systematically screened prior medication purchases recorded up to 10 years before diagnosis. Significant associations, adjusted for residual confounding, were further evaluated in the TriNetX network, where large propensity score-matched cohorts were compared for incident dementia following medication exposure or vaccination. Among all exposures assessed, strong protective associations were observed for atovaquone-proguanil, an antiprotozoal agent with established activity against Toxoplasma gondii, and for two different varicella-zoster virus (VZV) vaccines. These associations persisted after adjustment for demographic factors, comorbidities, and baseline healthcare utilization, and were independently reproduced in TriNetX across three strata of exposure age (50-59, 60-69, 70-79 years). In addition, T. gondii seropositivity was associated with increased dementia risk among individuals tested. In exploratory analyses, the magnitude of the association between atovaquone-proguanil and subsequent dementia appeared to differ according to prior VZV vaccination status, suggesting a possible interaction between protozoal suppression and antiviral immunity. Together, these findings provide population-level evidence consistent with a latent T. gondii-related mechanism in AD pathogenesis, and highlight testable targets for future mechanistic and interventional research.

Maternal immune activation (MIA) is a key environmental risk factor for neurodevelopmental disorders such as schizophrenia. MicroRNAs are critical regulators of brain development, yet their role in MIA-induced pathology remains unclear. We found that miR-322-5p was significantly upregulated in the prefrontal cortex of MIA-exposed offspring and directly targeted the 3' untranslated region of brain-derived neurotrophic factor (BDNF), inhibiting its expression. This upregulation impaired BDNF/TrkB/AKT signaling and reduced the synaptic protein PSD95, leading to hypoactivity, cognitive deficits, social impairments, and disrupted sensorimotor gating. Inhibition of miR-322-5p or overexpression of BDNF in the prefrontal cortex restored signaling and reversed both behavioral and molecular abnormalities. These results identify miR-322-5p as a key mediator of MIA-induced neuropathology via repression of BDNF signaling and suggest its potential as a therapeutic target in neurodevelopmental disorders.