Molecular Psychiatry最新文献

Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a comprehensive Mouse Microglia Atlas (MoMicA) to resolve conserved subtypes, delineate dynamic trajectories, and identify key regulators associated with AD pathology. We integrated ten single-cell and single-nucleus RNA-sequencing datasets from major AD mouse models, yielding 84,764 microglia for harmonized clustering, co-expression network analysis, and pseudotime inference, complemented by immune staining. Across models, AD was characterized by contraction of homeostatic microglia and marked expansion of DAM. MoMicA further delineated refined homeostatic and disease-associated subpopulations, including different homeostatic microglia subclusters and a stepwise progression from homeostatic microglia through activated response and pre-disease-associated states to disease-associated microglia. Network analysis highlighted lipid metabolism and inflammation as dominant AD-related programs and identified Fabp5 as a central hub gene within a DAM-associated lipid module. Multiplex immunofluorescence confirmed that Fabp5 is induced in Clec7a-positive DAM around amyloid plaques in two amyloidosis models. MoMicA therefore provides a valuable resource for dissecting the mechanistic roles of microglia in the onset and progression of AD.

Anhedonia is a core feature of major depressive disorder (MDD), yet links between peripheral molecular signatures and cortical network architecture remain poorly defined. We enrolled 210 participants, including 56 unmedicated MDD patients with high-anhedonia (HA), 61 with low-anhedonia (LA), and 93 healthy controls (HC). Morphometric similarity networks (MSNs) from structural MRI were compared between HA and LA. MSNs index individual-level network organization by quantifying inter-regional morphometric similarity. Regional MSN patterns were linked to Allen Human Brain Atlas using Spearman correlations with spin tests and a multi-K stability screen. Whole-blood RNA-seq (n = 199) was integrated with MSN features via sparse partial least squares-canonical correlation (sPLS-C), with key blood analyses repeated after leukocyte-composition adjustment. Gene Ontology over-representation and MAGMA gene-level analyses provided pathway context. HA showed greater MSN integration than LA, particularly within default-mode and somatomotor networks. MSN maps were negatively correlated with dopamine-transporter and kappa-opioid-receptor densities. Imaging-derived gene associations were enriched for regulation of Toll-like-receptor-3 signaling. In blood, sPLS-C revealed coupling between MSN features and a transcriptomic signature enriched for T-cell activation/differentiation and lymphocyte-apoptosis pathways. After composition adjustment, the pre-specified blood signature did not differ between HA and LA, indicating that between-group differences were largely composition-driven. As supportive genetic context, over-representation on MAGMA FDR-significant genes suggested protocadherin-mediated homophilic adhesion. Peripheral immune-redox pathway enrichment aligns with anhedonia-related cortical network alterations, whereas between-group blood differences are chiefly composition-driven. Adjusting for blood-cell composition is essential, this multimodal framework nominates immune-modulatory/redox targets and synaptic-adhesion biology for precision stratification and intervention.

Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD.

Mania/hypomania is pathognomonic of bipolar disorder (BD), yet early identification remains challenging. Impulsivity is a key feature of mania/hypomania and of externalizing disorders that may predispose to BD, but neural markers of impulsivity-related risk remain unknown. This study aimed to identify reward expectancy (RE)-related neural correlates of impulsivity facets, test moderation by current affective/anxiety symptoms, and determine whether such markers differentiate BD and/or externalizing disorders from low impulsivity individuals. Two independent BD-risk samples aged 18-30 years, including individuals with prior externalizing disorder diagnoses but not BD, were recruited; a euthymic BD group was also recruited. Impulsivity facets were assessed via Behavioral Activation System (BAS) and UPPS-P scales. Whole-brain regressions identified neural correlates of impulsivity facets during RE. Linear models tested replication and current affective/anxiety symptom moderation. ANCOVA compared neural activity among BD, externalizing, and non-BD/externalizing impulsivity tertile groups. Whole-brain regressions revealed a positive association between BAS Fun Seeking and pre-supplementary motor area (pre-SMA) activity (p_FWE = 0.003, k = 167), which replicated when depressive symptoms were covaried (discovery: β = 2.73, p < 0.001; replication: β = 0.88, p = 0.036; combined: β = 1.49, p < 0.001). A significant pre-SMA × depression interaction (β = -0.08, p = 0.037) indicated depressive symptoms attenuated the pre-SMA-Fun Seeking association. Group comparisons revealed greater pre-SMA activity in high-Fun Seeking (p < 0.001) and externalizing disorder groups (p = 0.039) versus low-Fun Seeking, with similar trends observed in BD once individuals taking medications, particularly benzodiazepines (p = 0.012), were excluded. Pre-SMA hyperactivity during RE is a robust neural correlate of BAS Fun Seeking, moderated by depression severity. This pattern represents a trait-linked neural marker of impulsivity associated with vulnerability to BD and externalizing disorders, informing early risk identification and intervention.

Autism Spectrum Disorder (ASD) is a complex and highly heterogeneous neurodevelopmental condition, typically emerging in early childhood and persisting throughout life. Its core symptoms-social communication deficits and restricted, repetitive sensory-motor patterns-exhibit dynamic trajectories across developmental stages, with distinct challenges arising at different ages. While substantial research efforts have been dedicated to pediatric ASD, the scientific focus remains comparatively limited for adult and geriatric populations, leaving their distinct needs less comprehensively addressed. This review begins with a concise overview of the epidemiology and etiology of ASD. We then examine age-dependent symptom evolution and associated challenges across the lifespan, from childhood to advanced age. Finally, we propose a stage-specific, individualized life-course support framework, outlining tailored strategies for distinct developmental phases. This framework transcends symptomatic management to empower functional resilience across the life trajectory, offering a roadmap for research and practice to serve the entire autism spectrum.

Suicide is the second leading cause of death for American adolescents and young adults and is transdiagnostic. Suicide risk is impacted by genetic and both distal and proximal environmental factors, particularly stress exposures. This review encompasses the past 10 years of research comparing biological measures between suicide decedents and control decedents and identifies studies focused on stress-related biological pathways, inflammation, neuroplasticity, and the serotonergic system as candidate contributors. Inclusion criteria for studies aimed to maximize confidence that reported biological differences are specific to suicide and independent of confounding psychiatric comorbidity, addressing ambiguity in previous work. The review revealed evidence for alterations in stress-related biological systems and decreased serotonergic tone among suicide decedents. Methodological and conceptual advances over the past decade have driven a shift from hypotheses-driven to data-driven approaches, including genomic, transcriptomic and methylomic analyses. While multi-omic studies have the potential to identify mechanistic molecular targets, to date findings lack interpretability. This review highlights the need for research in larger samples, across multiple brain areas, and in specific cell types to fill a gap in system biology-guided multi-omic studies. Lastly, incorporating poly-environmental stress exposure (exposomic) models in suicide postmortem research may elucidate mechanisms linking environmental stress and biological measures, potentially increasing the reproducibility of postmortem suicide studies.

Social cognitive deficits are common and impact functional outcomes in people with schizophrenia spectrum disorders (SSDs). Functional brain networks during task and rest show complex relationships with cognition. We aimed to identify relationships between social and non-social cognitive performance and functional connectivity during social processing and at rest across individuals with SSDs and healthy controls. Adults (N = 352; 195 SSDs, 157 controls) completed functional magnetic resonance imaging (fMRI) during the Empathic Accuracy (EA) task and rest, and cognitive assessments. Partial least squares correlation was used to identify latent dimensions (LDs) capturing multivariate relationships between functional connectivity and cognitive measures, evaluated using permutation testing, bootstrapping, and cross-validation. Two significant EA LDs were identified, explaining 73.6 and 9.1% of the variance. EA LD1 captured an association between better performance across cognitive measures and positive connectivity across networks implicated in processing dynamic multimodal and social stimuli. EA LD2 reflected an association between worse EA task performance and stronger positive connectivity between networks implicated in language and social processing. One significant resting-state LD was identified, explaining 85.6% of the variance and capturing an association between better overall cognition and visual, somatomotor, and subcortical connectivity, driven more by the SSD group. Overlapping and divergent connectivity patterns appear to covary with cognitive performance during social processing versus rest across SSDs and healthy controls. Our results support the value of task-based fMRI to identify dimensional functional connectivity patterns associated with particular social cognitive abilities, whereas resting-state connectivity may reflect broader relationships with cognition.