Translational Psychiatry最新文献

Schizophrenia is a heterogeneous psychiatric disorder with diverse clinical manifestations and complex biological mechanisms, in which age-at-onset (AAO) critically influences disease trajectory. Patients with early-onset schizophrenia (EOS; AAO < 18 years) present with more pronounced neurodevelopmental deficits and poorer long-term outcomes compared to adult-onset (AOS) cases. Previous genetic research on AAO and EOS has primarily focused on candidate genes and genome-wide association studies (GWAS). DNA methylation, an epigenetic mechanism influenced by the interplay between environmental and genetic factors, remains understudied, especially in the Chinese population. Peripheral blood DNA from 120 schizophrenia patients (49 EOS, 71 AOS) was analyzed using the Infinium MethylationEPIC v2.0 array. Differential methylated analyses were conducted for both EOS-AOS dichotomous comparison and continuous AAO, with stringent adjustment for age, sex, smoking, and estimated cell proportions. At a suggestive significance threshold (p < 5 × 10^-5), we identified 49 differentially methylated positions (DMPs) for EOS-AOS and 126 DMPs for AAO. Genes annotated to the identified DMPs included known schizophrenia and EOS-associated loci (such as ORMDL1, ANXA4, and TRRAP), as well as novel regions linked to cognitive function and neurodevelopment (such as AKAP8L, GPRC5C, and C4orf45). Enrichment analysis implicated key biological processes, including kinase signaling, cell cycle regulation, and microRNA pathways involved in apoptosis and oncogenesis. This study reveals novel differential DNA methylation patterns associated with EOS in the Chinese population and identifies key biological pathways potentially underlying its pathogenesis.

Sleep disturbances are among the most prevalent and early-emerging features of autism spectrum disorder (ASD), often preceding core behavioral symptoms. Despite their clinical relevance, the neurobiological mechanisms driving early-life sleep disruption in ASD remain poorly understood. Shank3, encoding a synaptic scaffolding protein at excitatory synapses, is one of the most well-established monogenic risk factors for ASD. Here, we systematically investigated sleep architecture and homeostatic regulation in juvenile Shank3^Δe11-21 rats, which lack Shank3 protein and display ASD-like behavioral and sensory phenotypes. EEG/EMG recordings revealed sex-specific abnormalities: males exhibited fragmented sleep with frequent brief arousals, whereas females showed prolonged wakefulness. Both sexes demonstrated reduced NREM sleep δ power, indicating diminished sleep depth. Following 6-h sleep deprivation, Shank3^-/- rats displayed blunted homeostatic rebound. Additionally, Clock and Bmal1 mRNA were significantly downregulated in prefrontal cortex and striatum, implicating circadian dysregulation within corticostriatal circuits. Collectively, these findings indicate that Shank3 deficiency leads to early-onset, low-quality sleep accompanied by impaired homeostatic and circadian regulation. This phenotype mirrors clinical sleep disturbances in children with ASD, supporting sleep dysfunction as an intrinsic, early feature of Shank3-related pathophysiology. Together with prior behavioral evidence, this study establishes the Shank3^Δe11-21 rat as a preclinical model for elucidating mechanisms of Shank3-related neurodevelopmental disorders and for evaluating potential early-life therapeutic interventions, including sleep-targeted strategies.

Chronic social isolation (SI) beginning in adolescence can lead to serious mental health problems and social skill deficits, potentially linked to altered development and function of the prefrontal cortex (PFC), a brain region frequently implicated in neuropsychiatric disorders. Oxytocin (OXT), a neuropeptide renowned for its prosocial effects, holds significant potential as an intervention for neuropsychiatric disorders. However, the efficacy of OXT in ameliorating mental disorders induced by adolescent-onset chronic SI remains uncertain. In this work, four-week-old C57BL/6 J mice were subjected to three months of SI, and subsequent alterations in their emotional and social behaviors were assessed. Thereafter, OXT was administered intranasally to SI mice to evaluate the effects of the intervention. The results show that exposure to SI leads to anxiety- and depression-like behaviors, deficits in social novelty recognition, and long-term impairments in social memory. OXT intervention effectively reversed the damage caused by SI, including improvements in behavioral deficits, increased expression of MAP-2 and PSD-95 in PFC, downregulation of abnormally elevated OXT receptor levels, reduction of neuroinflammation, and modulation of gut microbiota homeostasis. Our study confirms the therapeutic effects of OXT in reversing isolation-induced neuropsychiatric disorders and elucidates its potential regulatory mechanisms, offering important implications for clinical interventions.

Electroconvulsive therapy (ECT) is the most effective treatment for several particularly severe or pharmacotherapy-resistant psychiatric disorders, and a growing number of studies have investigated factors influencing the effectiveness of ECT. The objective of this article is to review the current evidence on clinical and biological markers potentially related to response to ECT and to outline perspectives for future research. In depressive disorders, the presence of clinical characteristics such as higher age, psychotic and psychomotor symptoms, and the absence of comorbid personality disorders are associated with a particularly good response to ECT. However, these clinical factors alone explain only a part of the variance of treatment outcome. Biomarkers at the genetic/epigenetic, immune inflammatory, and brain imaging levels are now providing promising and, in part, converging findings on both the mechanism of action and predictors of response to ECT. Taken together, these findings suggest a close relationship between specific clinical symptoms, the immune inflammatory, and neuroplastic mechanisms of ECT. While genetic studies consistently indicate a higher genetic risk load in patients referred for ECT, findings regarding the predictive value of polygenic risk scores and also epigenetic markers for ECT response remain inconsistent. In the future, combining clinical features and biomarkers could help define subgroups of psychiatric disorders with distinct pathophysiology and reliably predict treatment outcomes at the individual patient level. For now, it may be assumed that different and possibly age-dependent prototypical forms of depressive disorders exist, which are characterized by specific clinical (psychotic and psychomotor symptoms) and inflammatory markers (higher levels of IL-6 and CRP) and show a differential response to treatment modalities.

Major depressive disorder is a highly prevalent psychiatric condition characterized by diverse symptom profiles and variable treatment responses. The hippocampus has long been implicated in its pathophysiology, yet most human neuroimaging studies have treated it as a unitary structure, overlooking the distinct cytoarchitecture and connectivity of its subfields. Preclinical research demonstrates that subfields such as cornu ammonis 1 (CA1) and the dentate gyrus (DG) are differentially involved in stress susceptibility and antidepressant response. However, limited spatial resolution of conventional human neuroimaging has constrained in vivo characterization of these subfields and testing of translational hypotheses in humans. While advances in high resolution 3 tesla (T) imaging have improved subfield delineation, ultra-high field (UHF) MRI (7 T and above) extends these capabilities by combining whole-brain coverage with greater sensitivity to structural, functional and microstructural contrasts. This review synthesizes emerging applications of UHF MRI in depression, highlighting its advantages over conventional imaging approaches and early evidence for subfield-specific alterations. While most studies to date have focused on volumetric analyses, preliminary literature suggests structural and microstructural abnormalities in CA1 and DG, paralleling preclinical findings and implicating these subfields in network-level dysfunction and plasticity-related mechanisms. Future research should move beyond volumetric analyses to adopt more diverse MRI protocols capable of probing how subfield-specific architecture contributes to whole-brain networks and relates to clinical heterogeneity. UHF MRI offers a powerful platform to test mechanistic hypotheses derived from animal models, identify subfield-specific biomarkers, and ultimately guide personalized interventions targeting hippocampal circuits most relevant to individual symptom profiles.

Postpartum depression (PPD) is a significant global health concern affecting women, yet effective and innovative therapeutic targets remain limited. Although genome-wide association studies (GWAS) have identified genetic risk loci, their underlying mechanisms and translational potential remain poorly understood. Therefore, we integrated PPD GWAS data with protein quantitative trait loci from two independent datasets to identify risk genes through proteome-wide association studies (PWAS). Validation was performed using colocalization analysis and Mendelian randomization (MR). To assess the safety of genes as drug targets, phenome-wide MR (Phe-MR) was conducted using the UK Biobank disease data. Finally, we performed gene methylation analysis in PPD patients, alongside validation of expression in key brain regions including anterior cingulate gyrus (AnCg), dorsolateral prefrontal cortex, and nucleus accumbens, as well as in peripheral blood (whole blood and leukocytes), across depressive patients and chronic mild stress mice. Co-expression enrichment was used to identify biological pathways associated with risk genes. PWAS and colocalization analysis identified MKRN1 and CCDC92 as overlapping risk genes, with MKRN1 validated in MR. Phe-MR showed non-significant association between MKRN1 dysregulation and disease beyond depression and mood disorders, suggesting minimal off-target effects. Methylation analysis in PPD patients' blood revealed significant hypomethylation of MKRN1, consistent with expression analysis that confirmed its upregulation in AnCg and as a biomarker in blood. Enrichment analysis indicated MKRN1 involvement in immune-inflammatory pathways. Our study identified MKRN1 as a therapeutic target for PPD, integrating multi-omics evidence from genomics, proteomics, and druggable proteome profiling, and offering a promising path for targeted treatments.

Betel nut is the fourth most commonly used psychoactive substance globally and is particularly prevalent in the Asia-Pacific region. Betel nut chewing is closely associated with a variety of health hazards, including oral cancer, cardiovascular diseases, and metabolic syndrome. This article reviews the epidemiological characteristics, health hazards, neurobiological mechanisms, and intervention strategies of betel nut addiction. The major active component in betel nut, arecoline, leads to addiction by modulating the cholinergic, dopaminergic, and glutamatergic systems, with the involvement of the gut-brain axis and immune-inflammatory responses. In terms of intervention strategies, pharmacological treatments (such as nicotinic receptor modulators), neuromodulation techniques (such as real-time functional magnetic resonance imaging neurofeedback), cognitive-behavioral therapy, and public health policies have shown potential efficacy. Future research should focus on the development of precision medicine strategies and interdisciplinary integrated intervention models.

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.

Accumulating evidence suggests dysfunction of cerebellar-cerebral circuits in depression. However, the potential cellular and molecular alterations associated with depression in the cerebellum remain largely uncharacterized. While postmortem findings in the cerebral cortex indicate astrocyte dysregulation in depressed individuals who died by suicide (DS), the extent to which depression potentially alters cerebellar astrocytes is not well understood. In this study, two canonical astrocyte markers, glial fibrillary acidic protein (GFAP) and aldehyde Dehydrogenase-1 Family member L1 (ALDH1L1) were used to quantify cerebellar astrocyte subtypes, Bergmann glia (BG) in the Purkinje cell layer (PCL), velate astrocytes in the granule cell layer (GCL), and fibrous astrocytes in the white matter (WM). Purkinje cells (PCs) were also quantified due to their close association with BG. To assess potential dysregulation of astrocyte communication, we examined connexins, channel proteins essential in forming a functional network between astrocytes. Astrocytic connexins were visualized using single molecule in situ hybridization targeting connexin 30 (Cx30) and connexin 43 (Cx43), followed by immunolabeling for ALDH1L1. Our analysis revealed significant increases in ALDH1L1+ astrocyte densities in DS specific to the PCL compared to control individuals. Astrocytic connexins were significantly downregulated in DS, with Cx43 showing marked reductions in both PCL and GCL. Overall, our findings suggest that BG in the PCL and velate astrocytes in the GCL are particularly vulnerable in the depressive phenotype. Furthermore, this study supports previous findings in the cerebral cortex and extends astrocytic dysfunction to the cerebellum suggesting a widespread disruption of astrocyte-mediated communication across the brain in depression.

Lipids are highly abundant in the brain and play key roles in membrane regulation, neurotransmission, neurogenesis, and inflammation. The same processes are involved in neuromodulation mechanisms. While neuromodulation therapies have shown promising outcomes for treatment-resistant psychiatric disorders, the factors determining individual variability in treatment response remain poorly understood. Furthermore, the potential impact of neurometabolic factors in predicting response has been largely overlooked. This narrative review aims to evaluate the role of lipids in psychiatric neuromodulation. Particularly glycerophospholipids, sphingolipids and polyunsaturated fatty acids (PUFAs) have been described as important mediators. Current evidence suggests a bidirectional relationship between lipids and neuromodulation therapies such as electroconvulsive therapy (ECT), and repetitive transcranial magnetic stimulation (rTMS). Neuromodulation effects are associated with lipid metabolism changes, including phospholipids, sphingolipids, and fatty acids. ECT is associated with an increase in lipid peroxidation and alterations of cholesterol and fatty acid levels, while rTMS is associated with normalization of sphingolipids and phospholipids levels. Solely one study investigated the relation between deep brain stimulation and lipids, showing an association with sphingolipid metabolism. To our knowledge, this is the first comprehensive review to consolidate findings on the relationship between lipids and neuromodulation. By mapping this emerging field, these findings might be a first step towards investigating whether lipids could be a potential biomarker for response prediction in the future. As most findings are preliminary, with variability across studies, further investigation is warranted and current findings should be interpreted in the context of their limitations.