Translational Psychiatry最新文献

A variety of studies show the involvement of acid-sensing ion channel 1a (ASIC1a) in the modulation of stress, however, the precise underlying mechanisms remain unclear. In this study, we provided evidence that ASIC1a, the Ca²⁺-permeable cationic ion channel, was co-expressed with corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN). Downregulation of ASIC1a in the PVN CRH neuron decreased the hypothalamic-pituitary-adrenal (HPA) axis activity, which further ameliorated anxiety- and depression-related behaviors by reducing CRH neuron activity. In vitro, activation of ASIC1a elevated the intracellular Ca²⁺ concentration and promoted the expression of CRH by activating Ca²⁺/CaMKII/c-Fos signaling pathways. This study reveals a novel mechanism of the modulation of negative mood by ASIC1a and suggests a potential novel therapeutic target for stress-related diseases.

Methamphetamine use disorder (MUD) represents a substantial global health challenge, largely attributable to the absence of effective treatments stemming from limited understanding of its neurobiological mechanisms. This study aimed to investigate the structural brain alterations, trait impulsivity, and genetic factors underlying MUD. We conducted structural magnetic resonance imaging scanning and whole-exome sequencing on a cohort of 142 male participants (91 patients with MUD vs. 51 healthy controls). Voxel-based morphometry revealed a significant reduction in gray matter volume (GMV) in the left thalamus among MUD patients, which exhibited a negative correlation with motor impulsivity (MI). Mediation analysis further demonstrated that MI mediated the relationships between thalamic GMV, duration of drug use, and MUD severity. Gene- and gene set-based burden tests identified 72 genes and three biological pathways: Cytidine Analogs Cytotoxicity, Muscle Structure Development, and Nuclear Speck, that were significantly associated with thalamic volume. GO enrichment analyses of 362 common genetic variants indicated a significant involvement in ciliary and microtubule-based motility processes. Concurrently, KEGG pathway analyses highlighted cytoskeletal and extracellular matrix signaling pathways. Gene-environment interaction analyses revealed that thalamic volume was significantly influenced by the interaction between rs12729569 and METH use, as well as between rs2282440 and duration of use. These findings suggest the thalamus as a critical structural substrate that links impulse control with METH-related neurotoxicity, emphasizing the role of cytoskeletal dynamics and ciliary function. Genetic variants that influence thalamic vulnerability may serve as promising biomarkers for risk stratification and the development of personalized interventions in MUD.

The 15q11.2 BP1-BP2 copy number variant (CNV) has been associated with neurodevelopmental and psychiatric conditions and brain grey matter structure, but its effects on white matter microstructure (WMM) in mid-to-late adulthood to assess long-term neurobiological effects remain unclear. Understanding these effects is important for evaluating long-term neurobiological impacts across the lifespan. WMM parameters were extracted from UK Biobank diffusion magnetic resonance imaging data for 15q11.2 BP1-BP2 deletion (n = 126, mean age: 66 ± 8) and duplication (n = 131, mean age: 64 ± 7) carriers, as well as age- and sex-matched non-carriers (n = 1260 and n = 1310). We used multiple advanced diffusion approaches, extending beyond DTI, providing metrics on various spatial levels comparing the CNV carriers and non-carriers. All metrics were projected on the WM skeleton for further group comparisons. We present various atlas-derived region-level differences between 15q11.2 BP1-BP2 deletion carriers and non-carriers. These differences suggest altered microstructural organization in the corpus callosum, cingulum and hippocampus, uncinate fasciculus, indicated by lower diffusivity and higher fractional anisotropy, kurtosis, axonal water fraction, and intra-neurite volume fraction (absolute standardized effects > 0.22). Most significant differences across multiple diffusion approaches were detected in the corpus callosum. Our findings suggest that during mid- to-late life, WMM in the corpus callosum is affected by 15q11.2 deletion. Different diffusion approaches allowing for microscopic assessments of WM, beyond previous non-microscopic diffusion MRI based assessments, suggest altered axonal density or microstructural organization, potentially reflecting pathological axonal overgrowth and myelination abnormalities, adding explanations for observable developmental and psychiatric differences between deletion carriers and healthy controls.

Cocaine addiction is characterized by high relapse rates associated with glutamate dysregulation, presenting significant challenges for long-term treatment. N-acetylcysteine (NAC) has shown promise in preventing drug relapse by normalizing glutamate function, potentially mediated by glutamate 2/3 (mGlu2/3) receptor activation. This study investigated the therapeutic potential of NAC in reducing cocaine-seeking behavior using the self-administration model. After establishing stable cocaine self-administration and a 7-day abstinence period, rats received a single dose of NAC (100 mg/kg, i.p.) 30 min before the first extinction training session. NAC significantly reduced cocaine-seeking behavior on the first day of extinction but not in subsequent extinction sessions. Following extinction, tests for cue-induced reinstatement and spontaneous recovery were conducted. Results showed that NAC administration on the first day of extinction effectively reduced cocaine-seeking during the reinstatement test, with effects lasting at least 28 days. The mGlu2/3 antagonist LY341495 (1 mg/kg) fully blocked this enduring suppression of reinstatement without altering the immediate decrease in drug-seeking observed on the first day of extinction. Additionally, NAC administration on the initial extinction day also reduced context-induced reinstatement of cocaine-seeking behavior. These results indicate that NAC exerts its anti-relapse effects via mGlu2/3 receptors. A single NAC treatment combined with extinction training can produce lasting suppression of relapse, highlighting its therapeutic promise for addiction treatment.

Machine learning (ML) offers promise for suicide risk stratification in depressed youth, yet its clinical application remains methodologically challenging. Using prospective data from 602 Chinese patients aged 15-24 years collected between January 2022 and June 2023, we developed ML models to predict suicide attempts within 30 days after treatment. From 102 clinical and psychosocial predictors, only 30 suicide attempts (5.0%) were observed, resulting in a limited predictor-to-event ratio. Seven algorithms were trained on 70% of the sample (n = 421; 21 events) using 10‑fold cross‑validation and tested on the remaining 30% (n = 181; 9 events), with model selection emphasizing regularization and parsimony to reduce overfitting risk. Among the algorithms, the Support Vector Machine (AUC = 0.831) and Elastic Net (AUC = 0.811) achieved the best test performance, while more complex models such as random forests and deep learning exhibited poor generalization. A combined SVM + EN ensemble reached an AUC of 0.84 in cross‑validation and identified a high‑risk decile with a 20% suicide attempt rate compared to 3.6% among remaining patients (RR = 5.53), although confidence intervals were wide due to the small number of events. These findings demonstrate the technical feasibility of ML‑based short‑term risk stratification but also underscore important methodological constraints. When retrained using only 15 LASSO-selected predictors, the model's discrimination remained comparable (AUC = 0.82), supporting robustness against over-fitting. Low event counts limited model stability, cohort homogeneity and single‑country recruitment restricted generalizability, and the lack of temporal validation precluded assessment of model drift. Consequently, the models presented here should be viewed as proof‑of‑concept rather than evidence of clinical readiness, providing an empirical basis for future validation in larger and more diverse longitudinal cohorts.

Pupil-based biofeedback has been shown to enable healthy participants to volitionally control locus coeruleus-mediated arousal. The locus coeruleus is considered a critical player in the central stress circuitry and dysfunctions in the system, causing dysregulated arousal levels, have been tightly linked to neuropsychiatric disorders such as anxiety and stress-related disorders and stress-induced cardiovascular vulnerability. Yet, it remains unclear whether physiological and self-rated affective responses to emotional stimuli are influenced by volitional control of arousal levels. In this study, healthy participants were presented with emotional (negative) or neutral sounds while they self-regulated (i.e., up- and downregulated) pupil size and pupil-linked arousal levels, a skill acquired through prior pupil-based biofeedback training. While no immediate online effect of such self-regulation on self-rated affect experience was observed, greater gains in pupil downregulation training predicted reduced affect experiences, particularly in response to negative sounds. Furthermore, larger pupil dilation responses to sounds were found during both pupil size up- and downregulation compared to a non-regulatory control condition, potentially indicating regulatory effort associated with pupil self-regulation. However, heart rate responses significantly decelerated during sound presentation and concurrent pupil size downregulation, suggesting parasympathetic dominance. These results provide the first evidence that pupil-based biofeedback training may modulate both self-rated and physiological responses to emotional sounds to a certain extent, highlighting its potential as a tool for reducing hyperarousal and hyperresponsivity to emotional sounds, as seen in anxiety and stress-related disorders, through pupil-linked arousal self-regulation.

Prenatal maternal stress (PNMS) increases the risk for autism, and individuals with autism inconsistently exhibit increased or decreased volumes and functional connectivity of the whole amygdala and the whole hippocampus. Given heterogeneous structures of the amygdala and hippocampus and the heterogeneity of autism symptoms, it is worth examining how their subregions contribute to different autism phenotypes. T1-weighted and resting-state functional MRI data were acquired from 32 young adults of mothers who were pregnant during, or within 3 months of, the 1998 Quebec ice storm. Their broad autism phenotype (BAP) was self-reported, including aloof personality, pragmatic language impairment and rigid personality. This sample has a wide range of scores on the BAP Questionnaire. Volumes of the amygdala nuclei and hippocampal subfields were calculated. Seed-to-voxel analysis was applied to examine functional connectivity of the amygdala nuclei and hippocampal subfields with the rest of the brain, and linear regressions were implemented to examine associations of volume and functional connectivity with the three autism phenotypes. Primarily, we found that 1) rigid personality was associated with decreased left hippocampal cornu ammonis (CA)1 volume; 2) pragmatic language impairment was associated with decreased left hippocampal CA1 connectivity with the supplementary motor area, and increased right hippocampal CA4 connectivity with the left putamen; and 3) rigid personality was associated with increased right central amygdala connectivity with the left inferior lateral occipital cortex (LOC); and increased left hippocampal CA3 connectivity with the right superior parietal lobule, increased right hippocampal CA4 connectivity with the left superior LOC, and increased right hippocampal dentate gyrus connectivity with the left superior LOC. In contrast, we found no associations with aloof personality. Our results suggest that, within a sample exposed to PNMS, amygdala and hippocampal structure and function contribute differently to two different autistic-like characteristics, with hippocampus-motor connectivity explaining variance in communication impairment, and with hippocampal volume, amygdala- and hippocampus- sensory connectivity sharing the common mechanism in rigid behaviors. Given these links between brain and autistic-like traits, future research should examine whether brain volumes and connectivity mediate associations between PNMS and autistic-like traits in young adulthood.

Schizophrenia exhibits substantial clinical and neuroanatomical heterogeneity, yet conventional cross-sectional studies typically analyse patients at different disease stages as homogeneous groups, diluting pathological diversity. We applied the Subtype and Stage Inference (SuStaIn) algorithm to structural MRI data from 85 patients with schizophrenia and 224 healthy controls, integrating this with resting-state functional MRI analysis for the first time. SuStaIn identified two distinct neuroanatomical subtypes: Subtype0 demonstrated anterior-to-posterior progression with early frontal-limbic atrophy and prominent positive symptoms, while Subtype1 exhibited posterior-to-anterior progression originating in subcortical-occipital regions with greater social withdrawal. Disease progression stage correlated with functional connectivity in opposing directions-Subtype0 showed hypoconnectivity (ρ = -0.56) while Subtype1 exhibited hyperconnectivity (ρ = 0.70). These contrasting patterns may explain decades of contradictory functional connectivity findings in schizophrenia literature, as previous studies likely captured different subtypes at various disease stages. Our integrated structure-function approach reveals distinct disease trajectories that could inform subtype-specific therapeutic strategies.

Genetic and environmental factors contribute to depression. Among the latter, early life adversity and immune dysregulation have been consistently linked with depression. Childhood maltreatment (CM) is believed to induce immune dysregulation later in life. However, it is not known how CM might interact with genetic immune factors to contribute to the occurrence of depression. We investigated how genetic variability in 2370 genes from 20 immune pathways associates with a broadly-defined lifetime depression phenotype at gene- and pathway-level, and how this variability interacts with CM. Depression analysis was carried out in 13,309 individuals (1867 cases) from Generation Scotland (GS). CM interaction analysis was carried out in a subset of 749 individuals (99 cases) from GS and an independent sample of 509 individuals (96 cases) from the German BiDirect (BD) Study for which both genetic and CM data was available. Interactions with different types of CM were tested using the subscales of the childhood trauma questionnaire (CTQ). These results were meta-analyzed to obtain general gene-CM interactions. We found association of the GHR gene (false discovery rate -FDR- = 0.03, z = 4.2) and Reactome "RUNX1-regulated transcription of genes involved in myeloid cell differentiation pathway" (FDR = 0.016, beta = 1.2) with depression in GS. After meta-analysis, 56 immune gene-CM interactions were associated with depression (FDR < 0.05) in both GS and BD. These exert functions in hematopoiesis, pathogen recognition and stress responses, among others. Network analysis suggested macrophages as main expressing cell types. Our results underscore the involvement of hematopoietic alterations and immune gene-CM interactions in the development of depression.

NeuroHIV has emerged as a significant unmet challenge, manifesting as impairments in learning, memory, sensorimotor, and language in people living with HIV (PLWH). Despite the widespread use of antiretroviral therapy, the incidence of NeuroHIV remains high among PLWH. Microglial cells, as the main targets and reservoirs for HIV-1 infection, play crucial roles in sustaining HIV-1 persistence and contributing to neuroinflammation and neuroHIV pathogenesis. This review summarizes recent molecular studies that elucidate the role of HIV-1-related factors-such as the viral proteins trans-activator of transcription (Tat), gp120, and Vpr, HIV-1 RNAs, and associated microRNA and long non-coding RNAs and extracellular vesicles-in microglial activation through mechanisms including cellular senescence, ferroptosis, defective mitophagy, NLR family pyrin domain containing 3 activation, and NF-κB pathway modulation. These processes collectively lead to neuroinflammation and the development of NeuroHIV. This review presents the current understanding of non-replicative mechanisms in NeuroHIV, outlining challenges, shortcomings, and the current treatment status. Further, it identifies potential therapeutic targets linked to microglial activation. The overall goal is to stimulate further research into novel strategies for mitigating the neuroinflammatory processes driving cognitive decline.