Molecular Psychiatry最新文献

Autism spectrum disorder (ASD) is a heterogeneous developmental disconnection syndrome. Identifying circuit deficits is crucial for understanding ASD etiology, yet the involvement of multiple brain regions and genetic variations complicates this analysis. Here, using an AI-powered mapping platform, BM-auto (Brain Mapping with Auto-ROI correction), to analyze a Thy1-YFP reporter, we show that different ASD-associated mutations cause distinct circuit abnormalities but share common deficits in the piriform cortex, a region regulating olfactory discrimination and social behavior patterns. We analyzed the whole-brain distribution of the Thy1-YFP reporter in three ASD mouse models (Tbr1^+/-, Nf1^+/-, and Vcp^+/R95G). YFP signals revealed altered axonal projections and structural connectivity. We also found that Thy1-YFP⁺ cell numbers varied across brain regions, revealing deficits in the differentiation or maintenance of projection neurons. While each mutation caused unique connectivity alterations, sensory regions-including the visual, somatosensory, and piriform cortices-were recurrently affected. However, effects on the visual and somatosensory cortices varied between models. The piriform cortex was the only region consistently impaired, showing reduced YFP signals and fewer Thy1-YFP⁺ neurons across all three models. Furthermore, all three mutants exhibited common olfactory discrimination impairments. Manipulating piriform cortex activity altered social behavior patterns, highlighting its role in ASD-linked circuit dysfunction. These findings underscore the vulnerability of sensory regions-especially the piriform cortex-to ASD-related mutations, strengthening the notion that altered sensory experiences are common in ASD.

Opioid use disorder (OUD) remains a major public health crisis, underscoring the urgent need for safer and more effective treatments. Cannabinoid CB2 receptor (CB2R) agonists show therapeutic promise for neuropsychiatric disorders and pain, with minimal psychoactive effects by themselves, but their potential in treating OUD is not well defined. Here, we report that MRI-2594, a novel, highly selective CB2R agonist, reduced heroin self-administration and heroin-primed reinstatement of drug-seeking behavior in rats. MRI-2594 produced modest analgesia by itself without impairing oxycodone-induced analgesia, hyperlocomotion, or causing sedation. Local infusion of MRI-2594 into the ventral tegmental area (VTA) or nucleus accumbens (NAc) also inhibited heroin self-administration in rats. Systemically administered MRI-2594 reduced dopamine (DA) release in the NAc, as measured by fiber photometry. In DAT-Cre mice, MRI-2594 attenuated brain-stimulation reward driven by optogenetic activation of VTA DA neurons - an effect blocked by the selective CB2R antagonist MRI-2687. To confirm CB2R mechanism, we generated a new strain of CB2-KO-eGFP mice in which the CB2R coding region was replaced with an eGFP reporter. Immunostaining revealed CB2R-driven GFP expression in tyrosine hydroxylase (TH)-positive VTA DA neurons of CB2-KO-eGFP, but not wild-type, mice. Lastly, MRI-2594 inhibited heroin self-administration in wild-type but not CB2-KO-eGFP mice. These findings demonstrate that brain CB2Rs mediate the anti-addictive effects of MRI-2594 and highlight CB2R as a potential target for OUD therapy.

Stress is both an underlying and exacerbating factor in a wide range of neuropsychiatric disorders, from anxiety to major depressive disorder. Such stress-related behaviours are thought to be modulated, in part, by the receptors for the stress hormone cortisol. These receptors, namely the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), are highly conserved transcription factors that bind as homodimers to response elements in target genes. Although it has been shown that MR and GR can act as heterodimers as well, little is known regarding the physiological relevance of MR/GR heterodimerization. Here we tested the hypothesis that MR/GR heterodimerization is essential to mediate the behavioural effects of cortisol. For this purpose, we established mutant MRs and GRs that could selectively homo- or heterodimerize and expressed these receptors in zebrafish from an MR/GR double knockout line. Subsequent behavioural analysis revealed that cortisol induced hyperactivity, but only under conditions of MR/GR heterodimerization. To investigate the molecular targets of these heterodimers, we next performed RNA-sequencing, which showed that MR/GR heterodimers regulated the expression of genes involved in glutamatergic signalling. This was confirmed by CRISPR/Cas9-mediated gene editing of a response element in the gene encoding the metabotropic glutamate receptor 3, which abolished the cortisol-induced hyperactivity. Furthermore, pharmacological treatments showed that besides glutamatergic signalling, GABAergic and serotonergic signalling are involved as well. Taken together, this study establishes the physiological relevance of MR/GR heterodimerization, which appears to play a central role in eliciting behavioural alterations upon stress, by altering the activity of crucial neurotransmitter systems.

As the global prevalence of cannabis use disorder increases, there are concerns about its association with self-harm and suicide. We conducted a retrospective population-level study in Ontario, Canada of all individuals aged 15-105. Deliberate self-harm and deaths due to suicide were compared between individuals with an incident emergency department (ED) visit or hospitalization for cannabis use, matched with members of the general population (primary analysis) or people with an ED visit for alcohol use (secondary analysis), using adjusted hazard models. Models were adjusted for age and sex and further adjusted for pre-specified variables including sociodemographics, co-morbid mental and chronic health conditions and substance use. We followed 11,320,897 people of whom 85,108 (0.75%) had an incident cannabis-related hospital contact. We included a total of 861,291 people with a median follow-up of 5 (IQR 3-7) years in our primary matched analysis. People with a cannabis-related hospital contact had a 5.4-fold (adjusted Hazard Ratio [aHR] 5.35 95%CI5.04-5.67) increased risk of deliberate self-harm and a 9.2-fold (aHR 9.22 95%CI5.24-16.23) increased risk of death by suicide within 3 years relative to the general population. Among individuals with a cannabis-related hospital contact, the risk of self-harm was elevated in those with and without co-morbid mental health or substance use disorder. Sensitivity analyses excluding those with co-morbid mental health or substance use disorders continued to show increased risk of deliberate self-harm relative to the general population (aHR 7.18 95%CI6.26-8.23). In the secondary analysis, people with an alcohol related hospital contact were at a higher risk of self-harm relative to cannabis (aHR 1.22 95%CI1.18-1.26). These findings highlight that the growing prevalence of cannabis use disorder may have important implications for mental health, self-harm and suicide.

Psychosocial stress in women is a major public health concern, yet the intergenerational mechanisms linking maternal premating stress to offspring neuropsychiatric vulnerability remain incompletely understood. Here, female mice were exposed to chronic unpredictable mild stress (CUMS) prior to mating, and offspring were assessed for neurodevelopment, adult behavior, and multi-omics profiles. Premating stress induced neurodevelopmental delays and sexually dimorphic adult phenotypes: female offspring exhibited hyperactivity and social deficits, whereas male offspring displayed anxiety. Cerebellum cytokine levels were reduced in a sex-dependent manner. Maternal stress shifted offspring gut microbiota (GM) composition, with p_Proteobacteria as core taxa in females and p_Firmicutes in males, exhibiting sex-dependent and inverse shifts in microbial network connectivity. Male offspring showed marked metabolic alterations and enhanced maternal-offspring metabolic concordance. Integrated analyses of GM, metabolites, and cerebellum profiles identified sexually dimorphic network correlations, further supported by human data demonstrating maternal stress-induced, sex-dependent GM network remodeling. Lactoferrin (LF) intervention selectively rescued male anxiety but not female behavioral deficits, and in males specifically, reduced cerebellum pro-inflammatory cytokines, enhanced GM network connectivity, and enriched immune-related serum metabolic and cerebellum transcriptomic pathways. LF also suppressed Purkinje cell firing frequency in males and reinforced post-treatment connectivity across microbial, metabolic, and cerebellum transcriptional nodes. Collectively, these findings delineate a previously unrecognized sexually dimorphic neuro-microbiota-metabolic network underpinning intergenerational vulnerability and highlight microbiota-targeted modulation as a systems-level mechanistic framework for sex-specific prevention of maternal stress-associated neuropsychiatric disorders.

Schizophrenia (SCZ) is a severe neurodevelopmental mental disorder characterised by a complex and multifactorial disease aetiology. Patients can suffer from both positive symptoms (e.g. hallucinations) and negative symptoms (e.g. social withdrawal) as well as cognitive impairments. The former are currently discussed to be caused by a hyperdopaminergic state in the striatum, whereas for the latter a hypodopaminergic state in the prefrontal cortex (PFC) is hypothesised. However, the underlying mechanism of hypodopaminergic signalling in the PFC, especially via the mesocortical pathway, is currently not known to any great detail. By analysing the transcriptome of iPSC-derived dopaminergic neurons from SCZ patients, we found that genes involved in dopaminergic differentiation as well as in dopamine synthesis and transport were downregulated. Furthermore, the expression of the D2 subtype of the dopamine receptor (DRD2) was also decreased, suggesting a hypodopaminergic phenotype and disinhibition of neuronal activity. Calcium imaging of a purely SCZ co-culture of human dopaminergic and glutamatergic telencephalic neurons revealed increased activity of both types of neurons, which was selectively reduced by a DRD2 agonist. Further quantification of synapse marker densities indicated a loss of glutamatergic synapses both on NGN2 and ALN neurons, whereas dopaminergic synapses were unaffected. Using mixed co-cultures comprising glutamatergic/dopaminergic neurons from healthy controls and SCZ patients, calcium imaging identified SCZ-ALN neurons as a major driver of increased activity in SCZ. Thus, the proposed model may be useful for the study of hypodopaminergic phenotypes of schizophrenia.

Polygenic score (PGS) predictions of educational achievement are sizeable at the population level. Yet, population-level PGS predictions are environmentally confounded, due to gene-environment correlations, assortative mating, and population stratification. This confounding complicates the interpretation and application of PGS predictions of educational achievement. Here, we charted the variability of PGS predictions in N = 8115 dizygotic twins from UK, US, Swedish, and German samples aged 7 to 19 years. Population-level PGS predictions of educational achievement ranged from β = 0.16 to β = 0.37 across ages and countries. Discerning within- and between-family level estimates, we found that 10 to 65% of the population-level PGS predictions were due to environmental confounding, of which 29 to 100% were accounted for by family socioeconomic status. Variability in within-family and population-level PGS predictions was largely unsystematic across countries' school systems (multi-tiered vs. comprehensive) and children's ages. Therefore, interpretations regarding the sources of environmental confounding effects on educational achievement remain, at present, speculative.

Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer's, diabetes, and asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum.

Language disturbances are central features of serious mental illnesses, yet traditional clinical assessments often rely on subjective evaluation that may overlook subtle speech anomalies. This study employs natural language processing (NLP) to objectively analyze spontaneous speech in a transdiagnostic sample comprising individuals with affective (n = 119 Major Depressive Disorder, n = 27 Bipolar Disorder) and psychotic disorders (n = 37 Schizoaffective Disorder, n = 11 Schizophrenia), as well as healthy controls (n = 178). Participants provided approximately 12 min of speech elicited via four pictures from the Thematic Apperception Test, which were transcribed and analyzed for semantic and syntactic features. Explorative factor analysis identified three latent linguistic dimensions: (1) Syntactic Complexity, (2) Lexical Diversity and Fluency, and (3) Narrow Thematic Focus. These dimensions were differentially associated with clinical ratings of formal thought disorder and neuroanatomical measures obtained through structural and diffusion-weighted MRI. Notably, Syntactic Complexity and Lexical Diversity correlated with decreased fractional anisotropy (FA) in frontotemporal white matter tracts, while Narrow Thematic Focus was linked to reduced gray matter volume in the right posterior insula. Importantly, these associations persisted after controlling for diagnosis, medication status, and verbal IQ. These findings suggest that NLP-derived speech metrics can serve as sensitive indicators for language dysfunction in psychiatric conditions, offering a scalable approach to elucidate brain-behavior relationships and advance models of psychopathology.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications associated with prematurity. GM-IVH commonly results in neurodevelopmental impairments or neuropsychiatric disorders. However, GM-IVH has no successful treatment. Previous studies have shown that early intervention programs may have beneficial effects in preterm newborns (PT). Similarly, enriched environments (EE) increase neurogenesis and behavioral alterations in animal models. Therefore, we propose the study of the effects of long-term exposure to a complex EE in a murine model of induced GM-IVH. We analyzed brain pathological features and feasible markers of GM-IVH, as well as behavioral outcomes. In parallel, we analyzed the same plasma markers in PT with GM-IVH that followed an intervention program including parental bonding and stimulation. EE exposure limited brain atrophy, maintained the neuronal density, limited axonal damage and increased the neuronal complexity. Furthermore, neurogenesis was promoted and the inflammatory process was attenuated. Importantly, after the exposure to EE, cognition was improved, and the peripheral markers of brain damage, UCHL1 and plasma gelsolin, were also ameliorated. In line with this, plasma UCHL1 was early increased in patients with GM-IVH while plasma gelsolin was reduced and an overall reduction of peripheral markers was observed with time, both in Controls and in patients with GM-IVH. On the other hand, plasma tau levels were significantly reduced in those patients with GM-IVH that received parental support and nurturing environment. Altogether, our data show an improvement of pathological hallmarks, peripheral biomarkers and cognitive impairment associated with GM-IVH and support the beneficial effects of early intervention programs.