Translational Psychiatry最新文献

Childhood adversity increases risk for impaired social functioning later in life; however, neural pathways delineating this association are poorly understood. Different types of adverse interpersonal experiences (i.e., abuse, neglect) may impact neural pathways distinctly, resulting in unique consequences on social motivation and behavior in adulthood. Here, we investigated neural responses during the anticipation of social reward and punishment and their associations with childhood abuse and neglect in adults with a depressive and/or anxiety disorder and social impairment. Participants (N = 57) completed an fMRI social incentive delay task. In region-of-interest analyses, we examined activation in striatal regions when participants anticipated receiving potential social reward or avoiding social punishment in relation to self-reported childhood abuse and neglect. Individuals endorsing greater neglect during childhood demonstrated increased activation in the caudate (β = 0.359, p = 0.006) and putamen (β = 0.454, p < 0.001) during anticipation of social reward, while participants reporting greater abuse during childhood showed decreased activation in the same regions (β = -0.314, p = 0.024 and β = -0.341, p = 0.014, respectively). When both types of adversity were included in the same model, only neglect remained a significant predictor of putamen activation during social reward anticipation (β = 0.402, p = 0.009). No significant associations were observed between childhood trauma and activation during anticipation of social punishment. Findings reveal differential associations of childhood abuse and neglect with dorsal striatum activation during social reward anticipation in adults with anxiety and depression. Treatments targeting aberrant social reward processing may benefit patients who have experienced significant childhood adversity, and different approaches may be needed based on the type(s) of early adversity experienced.

The genetic heterogeneity of autism spectrum disorder (ASD) presents significant challenges in understanding its pathogenic mechanisms, as the genetic risk involves numerous common variants and rare de novo or inherited variants. Prior research has mainly focused on identifying rare variants and their impact on neurodevelopment and neuronal functions in cortical brain regions. By contrast, common variants, which contribute substantially to ASD heritability, remain understudied, suggesting a need to consider both variant types to understand ASD's genetic mechanisms. Previous studies have also implicated subcortical brain regions and peripheral digestive and immune systems, but tissue-specific mechanisms remain unclear. We address these knowledge gaps by identifying gene networks, pathways, and key regulators informed by ASD common variants in brain and peripheral tissues, further examining whether these networks also capture genes informed by rare variants. Our approach integrates genome wide association study (GWAS) summary statistics, tissue-level genetics of gene expression, and gene coexpression and transcriptional regulatory networks across ~50 tissues. Our multitissue, multiomics analysis reveals that key brain regions and networks crucial for synaptic signaling and neurodevelopment are enriched for both rare and common variants, whereas peripheral tissues, such as the digestive and immune systems, are primarily informed by common variants. This partitioning of key tissues and biological pathways into core (targeted by both variant types) and modifying components provide insight into ASD heterogeneity. We also identified central gene network regulators, such as SYT1 and ADD2, which may orchestrate the effects of both common and rare ASD genetic risk factors on ASD pathogenesis.

Cocaine use disorder (CUD) is a neuropsychiatric disorder marked by compulsive drug-seeking and loss of control over cocaine intake, with women experiencing a faster addictive development and greater adverse outcomes despite lower incidence compared to men. Currently, there are no effective pharmacological treatments for CUD. Cannabidiol (CBD), a multitarget compound acting mainly on mediators of the expanded endocannabinoid system, has emerged as a potential therapeutic agent for substance use disorders. Though its effects have been researched in preclinical studies with males, its role in females remains underexplored. Here, we investigated the effect of CBD on distinct phases of cocaine-seeking and taking behaviour using the intravenous self-administration (SA) paradigm in female mice. First, CBD's pharmacological profile was evaluated on anxiety-like and cognitive-task models. Consequently, animals received CBD at 10 or 20 mg/kg to assess its effects on the acquisition of cocaine-consummatory behaviours and compulsive drug-seeking following association to negative consequences like an electric foot-shock. Our findings reveal that CBD modulates cocaine-seeking behaviour in a dose-dependent manner: 10 mg/kg CBD attenuated the acquisition of SA by alteration of reward- and cognitive-related markers within the mesocorticolimbic pathway. Conversely, 20 mg/kg increased cocaine consumption post-punishment but reduced cocaine-seeking upon re-exposure to punishment-associated cues and induced an upregulation of Htr1a expression in the medial prefrontal cortex. Parallel studies in males found no effects after punishment. These results highlight the complex, dose-dependent effects of CBD on cocaine consumption patterns and underscore its potential as a modulator of specific neurobehavioral processes in CUD in female mice.

The endocannabinoid ligand anandamide (AEA) plays a role in fear extinction, the conceptual foundation of the gold standard treatment for posttraumatic stress disorder (PTSD), exposure-based psychotherapy. Converging evidence from animal models and non-clinical human studies highlights the potential to enhance fear extinction pharmacologically by inhibiting the AEA catabolic enzyme, fatty acid amide hydrolase (FAAH). However, in our randomized clinical trial (n = 100), a FAAH inhibitor did no better than placebo at enhancing the response to exposure-based therapy in PTSD. Here, we used functional magnetic resonance imaging to investigate the neurobiological effects of FAAH inhibitor treatment on resting-state functional connectivity and the neural correlates of emotional processing (n = 76 scanned). We found that greater symptom improvement was significantly related to lower functional connectivity between ventromedial prefrontal cortex (vmPFC) and right dorsolateral prefrontal cortex (dlPFC), as well as lower task activation of the right dlPFC. Further, we found that self-reported symptoms at the time of scan were associated with increased functional connectivity of the vmPFC and the amygdala across the cortex (mainly in the ventral attention network and sensorimotor network, respectively). However, while we confirmed that 4 weeks of FAAH inhibition significantly increased AEA, there were no significant differences in functional connectivity or task activation between treatment groups. These findings suggest that FAAH inhibition does not affect intrinsic functional connectivity or emotional task response in PTSD, and that the dlPFC may play an important role in the response to exposure-based psychotherapy.

Low titers of blood circulating natural anti-NMDAR1 autoantibodies were reported in ~10% of the general human population. Their potential effects on NMDAR functions in the brain, however, remain unknown. We developed a new method to more accurately quantify these low titers of natural anti-NMDAR1 autoantibodies. After quantifying natural anti-NMDAR1 autoantibodies in the plasma of 324 subjects (163 healthy controls; 161 Alzheimer's disease (AD) patients), I found that AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies have significantly (p value: 0.0015) higher scores of Mini-Mental State Examination (MMSE score: 23.5) than AD patients carrying lower levels of natural anti-NMDAR1 autoantibodies (MMSE score: 21.4). No significant differences in MMSE scores were, however, found between healthy controls with either higher or lower levels of natural anti-NMDAR1 autoantibodies, indicating little harmful effect of the autoantibodies. Consistently, superior cognitive performances were found in AD patients carrying higher levels of natural anti-NMDAR1 autoantibodies in comparison with AD patients carrying lower levels of the autoantibodies. Although this association is intriguing, a causal relationship between natural anti-NMDAR1 autoantibodies and neuroprotection has not yet been established. Since anti-NMDAR1 autoantibodies can bind NMDA receptors to suppress glutamate excitotoxicity in the brain, natural anti-NMDAR1 autoantibodies may have neuroprotective effects against cognitive decline in AD patients.

Postpartum Psychosis (PP) is a severe and understudied perinatal mental illness which disproportionately affects women with bipolar disorder (BD). A relationship between sleep disturbance and PP is often assumed, but is poorly understood. From a cohort of 2099 individuals with BD, 343 parous women were identified and screened for perinatal psychiatric complications. We compared 117 women who developed PP with 226 who did not. Polygenic Risk Scores (PRS) for BD, schizophrenia, insomnia, short sleep, long sleep, sleep efficiency and sleep duration were computed using PRS-CS. Logistic regression was used to model the effect of each PRS on PP. Higher PRS for insomnia and short sleep were associated with reduced risk of PP. Individuals in the lowest decile for insomnia PRS (RR 1.96, 95% CI 1.25-3.07, p = 3.50 × 10⁻³) and short sleep PRS (RR 2.23, 95% CI 1.40-3.54, p = 7.94 × 10⁻⁴) had approximately double the risk of PP than individuals in the highest decile. The other PRS were not associated with PP. Mendelian Randomisation analyses did not support a causal relationship between sleep traits and PP. However, we demonstrate that the integration of PRS with bipolar subtype can improve prediction accuracy. Individuals with genetic vulnerability to insomnia or short sleep may develop a heightened tolerance to sleep disruption earlier in life, mitigating the impact of childbirth on mood. These findings suggest that genetic susceptibility to sleep disturbance may be important in the aetiology of PP, offering a new potential avenue for risk stratification and targeted prevention.

Transcriptomic studies of post-mortem brain samples in schizophrenia (SCZ) and bipolar disorder (BD) have primarily focused on messenger RNAs (mRNAs) but have given limited attention to small non-coding RNAs (sncRNAs). In this study, we present our analyses of sncRNA profiles from the prefrontal cortex of SCZ and BD cases and controls (53 SCZ cases, 40 BD cases, 77 controls), which we sourced from the Icahn School of Medicine at Mount Sinai and the NIMH Human Brain Collection Core brain banks. Corresponding mRNA-seq data were obtained from the CommonMind Consortium. Using a state-of-the-art pipeline, we mapped reads and determined differentially abundant and co-expressed sncRNAs and mRNAs, adjusting for known and hidden confounders. Across samples, 98% of all sncRNAs comprised miRNA isoforms (60.6%), tRNA-derived fragments (17.8%), rRNA-derived fragments (11.4%), and Y RNA-derived fragments (8.3%). In SCZ, 15% of the identified sncRNAs exhibited significant fold changes (FCs), with many also altered in BD, albeit to a lesser extent. For miRNAs, the FCs correlated strongly with the presence of non-templated nucleotides to their 3'-ends, independently of miRNA identity or locus of origin. Disease- and age-associated sncRNAs and mRNAs revealed accelerated aging in both SCZ and BD. Co-expression analyses also revealed, for the first time, disease-independent associations of many isomiRs, tRFs, rRFs, and yRFs with critical brain processes. These findings suggest complex and previously uncharacterized roles for novel classes of regulatory sncRNAs in synaptic signaling, neurogenesis, memory, behavior, and cognition.

Schizophrenia genome-wide association studies (GWASes) have identified >250 significant loci and prioritized >100 disease-related genes. However, gene prioritization efforts have mostly been restricted to locus-based methods that ignore information from the rest of the genome. To more accurately characterize genes involved in schizophrenia etiology, we applied a combination of highly-predictive tools to a published GWAS of 67,390 schizophrenia cases and 94,015 controls. We combined both locus-based methods (fine-mapped coding variants, distance to GWAS signals) and genome-wide methods (PoPS, MAGMA, ultra-rare coding variant burden tests). We extracted genes that 1) are targeted by existing drugs that could potentially be repurposed for schizophrenia, 2) are predicted to be druggable, or 3) may be testable in rodent models. We prioritized 101 schizophrenia genes, including 15 that are targeted by approved or investigational drugs (e.g., DRD2, GRIN2A, CACNA1C, GABBR2). Of these, 7 have never been tested in clinical trials for schizophrenia or other psychiatric disorders (e.g., AKT3). Seven genes are not targeted by any existing small molecule drugs, but are predicted to be druggable (e.g., GRM1). We prioritized two potentially druggable genes in loci that are shared with an addiction GWAS (PDE4B and VRK2). We curated a high-quality list of 101 genes that likely play a role in the development of schizophrenia. Developing or repurposing drugs that target these genes may lead to a new generation of schizophrenia therapies. Rodent models of addiction more closely resemble the human disorder than rodent models of schizophrenia. As such, genes prioritized for both disorders could be explored in rodent addiction models, potentially facilitating drug development.

SARS-CoV-2 infection in pregnancy has become common, yet very little is known about the impact of prenatal exposure on child development. Our objective was to examine the impact of infection with SARS-CoV-2 during pregnancy on child neurodevelopment in the first years of life. We conducted a longitudinal prospective cohort study among a diverse population of 69,987 children born January 2020-September 2021 in Northern California to members of an integrated healthcare system. Maternal SARS-CoV-2 infection during pregnancy was confirmed by polymerase chain reaction (PCR) test. All neurodevelopmental disorders (NDD) diagnosed in children by December 2023 were identified, including autism spectrum disorder (ASD), speech/language delay, and motor delay. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CIs), with adjustment for maternal sociodemographic and clinical characteristics, SARS-CoV-2 vaccination status during pregnancy, and child sex. A total of 2777 (3.97%) pregnant individuals had PCR-confirmed SARS-CoV-2 infection during pregnancy. Among 69,987 children aged 27-48 months, 12,006 (17.15%) were diagnosed with NDD; 2724 (3.89%) with ASD, 10,047 (14.36%) with speech/language delay, and 2716 (3.88%) with motor delay. Maternal infection with SARS-CoV-2 during pregnancy was not associated with an increased risk of speech/language delay or motor delay but was associated with an elevated risk of ASD among females (aHR = 1.44, 95% CI 1.05-1.97) but not males (aHR = 1.04, 95% CI 0.83-1.31). Prenatal exposure to SARS-CoV-2 infection may increase risk for autism spectrum disorders among females. Future studies are needed to confirm and extend these findings.

Adverse childhood experiences (ACEs) are associated with persistent mental health risks and brain structural differences across adulthood, yet their long-term neurobiological relevance in aging populations remains unclear. Given that ACEs are common and societies are aging, understanding how early adversity relates to mental and brain health across the lifespan is an important goal. This preregistered study examined whether ACEs are associated with mental health symptoms in mid- to late adulthood, and whether regional brain structure may account for part of this relationship. Cross-sectional data of the Hamburg City Health Study were used, involving participants aged 46-78 years with available magnetic resonance imaging data (N_total = 2 624; eligible: n_{analysis sample} = 1 900). Mental health status was quantified using the Patient Health Questionnaire-9 and the General Anxiety Disorder-7 questionnaire, while ACEs were assessed using the 10-item ACE-questionnaire. Predefined regions of interest (ROI) were the hippocampus, amygdala, and dorsolateral prefrontal cortex. Bayesian statistical analysis provided strong evidence for an association between ACEs and both mental health outcomes but did not confirm the hypothesized mediation by ROI-level brain morphology. Exploratory whole-brain voxel-based morphometry revealed significant regional grey matter volume (rGMV) reductions in individuals with 3 or more ACEs, affecting bilateral limbic and frontal regions-including the nucleus accumbens, gyrus rectus, and insula. These reductions were more pronounced and widespread in individuals with 4 or more ACEs, extending to areas in the dorsolateral and medial prefrontal cortex, anterior cingulate cortex, inferior parietal and temporal gyri, occipital cortex, and cerebellum. Notably, no increases in rGMV were observed for any ACE group. This suggests a dose-dependent effect, with 4 or more ACEs marking a potential threshold for more distributed neuroanatomical alterations. These results derived from a representative general population study extend the understanding of the possible effects of ACEs by providing evidence that structural changes associated with ACEs could last into mid and late adulthood similarly to mental health outcomes.