Translational Psychiatry最新文献

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.

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.

Epidemiological research suggests that maternal immune activation (MIA) during early gestation is a significant risk factor for neurodevelopmental and psychiatric disorders in offspring. Epigenetic factors and chromatin-related phenomena remain highly dynamic throughout prenatal and early postnatal development, offering a substrate through which environmental insults can exert lasting effects on gene regulation. Here, we used a mouse MIA model induced by infection with a mouse-adapted influenza A/WSN/33 (H1N1) virus to investigate the long-term molecular consequences of maternal infection on adult offspring. To separately assess prenatal and postnatal effects of MIA, we cross-fostered half of the pups from each influenza-infected or mock-treated dam at birth. We then profiled histone modifications (H3K27ac, H3K4me3) and transcriptome changes in neuronal nuclei isolated from the frontal cortex of adult offspring. Our results revealed considerable overlap between the prenatal and postnatal effects of MIA on enhancer activity, suggesting a sustained regulatory trajectory across developmental stages. Prenatal MIA was specifically associated with changes in gene regulatory elements related to forebrain and telencephalon development, while postnatal MIA primarily affected pathways involved in axonogenesis and synapse organization. Cross-species enrichment analysis further revealed that MIA-responsive enhancers and promoters are significantly enriched at GWAS loci for neuropsychiatric disorders. Together, these findings support a model in which MIA contributes to disease risk through enduring epigenetic reprogramming of gene regulatory networks in the developing brain.

Single Prolonged Stress (SPS) is a widely used rodent model for investigating the consequences of acute traumatic stress, but outcomes in mice are often variable across strains and behavioral domains. Because corticosterone (CORT) release is a central feature of the stress response, we combined SPS with post-stress CORT administration (SPS + CORT) to capture this hormonal component and unmask latent phenotypes. Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are highly expressed in the dorsal CA1 (dCA1) hippocampus, where they regulate neuronal excitability. We previously demonstrated that acute CORT enhances hyperpolarization-activated current (I_h) in vitro; here, we tested its in vivo contribution to stress-related behavioral and physiological outcomes. Male mice (8-9 weeks old) were exposed to SPS followed by vehicle or CORT. Behavioral assays-including the open field, Y-maze, and contextual fear conditioning-revealed that SPS + CORT mice displayed impaired spatial working memory and deficits in contextual recall and fear extinction, resembling core PTSD-like features. Whole-cell recordings from dCA1 neurons showed decreased input resistance, reduced action potential firing, and elevated I_h, which were normalized by the HCN channel blocker ZD7288. Overexpression of HCN1 in SPS mice reproduced both behavioral and physiological phenotypes seen in SPS + CORT mice, whereas genetic deletion of HCN1 in SPS + CORT mice reduced I_h and rescued the behavioral abnormalities. Together, these findings identify HCN1 channels as a critical mediator linking post-stress glucocorticoid signaling to maladaptive hippocampal plasticity and PTSD-like outcomes.

The habenula is a small epithalamic structure composed of two distinct subregions, the medial (MHb) and lateral (LHb) habenula. It serves as a critical hub for integrating fronto-limbic and brainstem signals to regulate motivation, mood, and reward processing. Therefore, it is unsurprising that dysfunction of the habenula has been implicated in several mood disorders including major depressive disorder (MDD), a debilitating mood disorder marked by low mood and feelings of hopelessness. This review synthesizes recent advances in understanding the habenula's neurocircuitry, molecular landscape, and role in MDD pathophysiology, while evaluating its potential as a therapeutic target. Specifically, emerging evidence highlights subregion-specific pathology. Indeed, in MDD and in animal models of depression, the MHb has been shown to exhibit marked downregulation of calcium-dependent activator protein for secretion 2 (CAPS2) and deficits in nicotinic acetylcholine receptor-mediated signaling. While in the LHb, dysregulated expression profiles of inward-rectifying potassium channel Kir4.1, the β isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIβ), protein phosphatase 2 A (PP2A), and small nucleolar RNA SNORA69 have been found in animal models of depression and MDD postmortem studies. Structural imaging and postmortem neurohistological studies in MDD patients have further revealed habenular volume changes, reduced neuronal cell counts, diminished cell area, and abnormal functional connectivity. As research unravels the habenula's complexities, its potential in treating mood disorders grows increasingly salient, offering new avenues for intervention in mental health.

The dorsolateral prefrontal cortex (DLPFC) is a principal target for transcranial magnetic stimulation (TMS) in treating major depressive disorder, with therapeutic effects thought to be mediated by its connectivity with the subgenual anterior cingulate cortex. As both regions are involved in autonomic regulation, short-term heart rate changes following DLPFC stimulation may serve as physiological markers to identify stimulation targets. We employed neuro-cardiac guided TMS in a cohort of healthy participants to examine the effects of stimulation intensity and DLPFC target specificity on heart-brain coupling (HBC). We used generalized additive models to assess nonlinear effects of stimulation intensity and target location on HBC, while accounting for pain ratings and other side effects. Intra-subject repeatability across three sessions was evaluated using intraclass correlation coefficients. We observed a non-linear modulation of HBC depending on stimulation intensity and target location, with greater effects at the F3 lateral and F3 posterior targets compared to sham. By evaluating these effects across sessions within participants, we demonstrate the robustness of our results beyond the influence of pain and other side effects on HBC modulation. Exploratory analyses of the directionality show a consistent decrease in HR only at the F3 lateral target with suprathreshold stimulation. These results demonstrate that HBC is modulated in a target- and intensity-specific manner, with particularly consistent effects at F3 lateral sites within the DLPFC. The findings enhance the understanding of TMS-modulated heart-brain interactions, offering a potential framework for optimizing individualized rTMS treatment protocols for depression.

Background: Mitochondrial dysfunction has been implicated in major depressive disorder (MDD), but reliable, measurable biomarkers remain elusive. As a minimally invasive and quantifiable biomarker, circulating cell-free mitochondrial DNA (ccf-mtDNA) in blood offers potential for objective assessment of mitochondrial stress in MDD. However, evidence linking regarding the association between ccf-mtDNA levels and MDD is limited and inconsistent.

Methods: We systematically searched eight databases, including PubMed, EMBASE, and major Chinese repositories. Thirteen studies with 1370 participants (837 individuals with MDD and 533 controls) were included per PRISMA guidelines. P-values were synthesized using the Lipták-Stouffer Z-score method. Sensitivity and fail-safe N analyses assessed the robustness of the findings and publication bias, and stratified analyses examined the effects of age, antidepressant use, and geographic region.

Results: Across studies, elevated blood ccf-mtDNA levels were significantly associated with MDD (p = 0.013). Stratified analyses revealed stronger associations in older adults (≥60 years old; p = 0.0009), unmedicated patients (p = 4.99 × 10⁻⁶), and North American cohorts (p = 4.29 × 10⁻¹¹), but not in younger individuals (p = 0.83), medicated patients (p = 0.97), and Asian/European samples (p = 0.72, p = 0.99). Sensitivity analyses indicated moderate instability overall but confirmed data robustness in key subgroups.

Conclusions: This is the first meta-analysis to establish a significant link between elevated blood ccf-mtDNA and MDD, highlighting age and antidepressant exposure as critical modulators. These findings support the potential of blood ccf-mtDNA to serve as a biomarker for late-life and drug-naïve depression, with implications for objective diagnosis and personalized treatment.