Yixuan Ma, Kiran Girdhar, Gabriel E Hoffman, John F Fullard, Jaroslav Bendl, Panos Roussos
{"title":"Sex differences in brain cell-type specific chromatin accessibility in schizophrenia.","authors":"Yixuan Ma, Kiran Girdhar, Gabriel E Hoffman, John F Fullard, Jaroslav Bendl, Panos Roussos","doi":"10.1016/j.biopsych.2025.09.016","DOIUrl":"10.1016/j.biopsych.2025.09.016","url":null,"abstract":"<p><strong>Background: </strong>Our understanding of the sex-specific role of the non-coding genome in serious mental illnesses, particularly schizophrenia (SCZ), remains largely incomplete.</p><p><strong>Methods: </strong>To address this gap, we explored sex differences in 1,393 chromatin accessibility profiles, derived from neuronal and non-neuronal nuclei of two distinct cortical regions from 234 cases with serious mental illness and 235 controls.</p><p><strong>Results: </strong>We identified sex-specific enhancer-promoter interactions and showed that they regulate genes involved in X-chromosome inactivation (XCI). Additionally, examining chromosomal conformation allowed us to identify sex-specific cis- and trans-regulatory domains (CRDs and TRDs). Co-localization of sex-specific TRDs with schizophrenia common risk variants pinpointed male-specific regulatory regions controlling a number of metabolic pathways. Moreover, enhancers from female-specific TRDs were associated with two genes known to escape XCI-XIST, which encodes a long non-coding RNA (lncRNA) that coats the X chromosome and initiates XCI, and JPX, a regulatory lncRNA that activates XIST transcription-underlying the importance of TRDs in deciphering sex differences in schizophrenia.</p><p><strong>Conclusions: </strong>Overall, these findings provide extensive characterization of sex differences in the brain epigenome and disease-associated regulomes.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kangjoo Lee, Jie Lisa Ji, Markus Helmer, John D Murray, John H Krystal, Alan Anticevic
{"title":"A framework for advancing mechanistic neuro-behavioral biomarkers in psychiatry.","authors":"Kangjoo Lee, Jie Lisa Ji, Markus Helmer, John D Murray, John H Krystal, Alan Anticevic","doi":"10.1016/j.biopsych.2025.09.013","DOIUrl":"https://doi.org/10.1016/j.biopsych.2025.09.013","url":null,"abstract":"<p><p>Neuropsychiatry has yet to surmount the fundamental challenge of mapping behavioral pathology to its underlying neural pathology. This gap limits the development of treatments for specific circuit pathologies, despite the great potential of neuroimaging measures. We show that the field may be moving towards refining limited statistical frameworks, while clinically translatable solutions could emerge with broader considerations. We posit that the failure to operate within a formalism that defines falsifiable parameters may have hindered progress. Here we propose a provisional formalism with the intention to bring into focus elements that seem necessary to advance the development of precision treatments in psychiatry. Specifically, we propose that this formalism should consider three defining axes: i) type of mechanism; ii) severity of mechanism; and iii) time. These three axes define a 3-dimensional dynamic mechanism complexity space. In turn, we posit that at any point in this mechanism complexity space there are embedded neuro-behavioral sub-spaces or 'geometries' for neural-to-symptom variation, which themselves are multi-dimensional and dynamic. This formalism provides for the mapping of the mechanism complexity space to a neuro-behavioral sub-space. Furthermore, we articulate how this formalism accommodates integration of spectra from genetics and systems biology (transcriptomics, epigenomics, etc.) to neural mechanisms, symptom variance and ultimately taxons of mental illness (i.e. categories). Finally, we argue that this formalism creates an opportunity to evaluate different types of treatment development that map onto dynamically evolving mechanisms of illness that are likely a hallmark feature of neuropsychiatric illness.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Autoimmune Psychosis: Progress, Problems, and the Path Ahead","authors":"Thomas A. Pollak","doi":"10.1016/j.biopsych.2025.08.008","DOIUrl":"10.1016/j.biopsych.2025.08.008","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"98 9","pages":"Pages 648-649"},"PeriodicalIF":9.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Shining a Light on the Earliest Symptoms of Psychosis","authors":"Paul C. Fletcher , Trevor W. Robbins","doi":"10.1016/j.biopsych.2025.08.006","DOIUrl":"10.1016/j.biopsych.2025.08.006","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"98 9","pages":"Pages 652-653"},"PeriodicalIF":9.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pleiotropy in Multitrait Genome-Wide Association Studies: Approaches and Insights From Schizophrenia–Cognition Analyses","authors":"Cue Hyunkyu Lee","doi":"10.1016/j.biopsych.2025.08.004","DOIUrl":"10.1016/j.biopsych.2025.08.004","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"98 9","pages":"Pages 650-651"},"PeriodicalIF":9.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Briana K Chen, Michelle Jin, Gergely F Turi, Victor M Luna, Abhishek Shah, Taylor Moniz, Margaret E Shannon, Michaela Pauers, Brenna L Williams, Vananh Pham, Holly C Hunsberger, Alain M Gardier, Indira Mendez-David, Denis J David, Christine A Denny
{"title":"A tale of two receptors: simultaneous targeting of NMDARs and 5-HT<sub>4</sub>Rs exerts additional effects against stress.","authors":"Briana K Chen, Michelle Jin, Gergely F Turi, Victor M Luna, Abhishek Shah, Taylor Moniz, Margaret E Shannon, Michaela Pauers, Brenna L Williams, Vananh Pham, Holly C Hunsberger, Alain M Gardier, Indira Mendez-David, Denis J David, Christine A Denny","doi":"10.1016/j.biopsych.2025.09.011","DOIUrl":"10.1016/j.biopsych.2025.09.011","url":null,"abstract":"<p><strong>Background: </strong>Serotonin (5-HT) receptors and N-methyl-D-aspartate receptors (NMDARs) have been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of (R,S)-ketamine, an NMDAR antagonist, and prucalopride, a 5-HT type IV receptor (5-HT<sub>4</sub>R) agonist, would have additional effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.</p><p><strong>Methods: </strong>A single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis.</p><p><strong>Results: </strong>A combination of K+P, given before or after stress, exerted additional effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC.</p><p><strong>Conclusions: </strong>Our results indicate that K+P has extended benefits, in comparison to K or P alone, for combating stress-induced pathophysiology at the behavioral and neural level. Our findings provide preliminary evidence that future studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Task and resting state fMRI modelling of brain-behavior relationships in developmental cohorts.","authors":"Lucina Q Uddin, Hugh Garavan","doi":"10.1016/j.biopsych.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.biopsych.2025.09.012","url":null,"abstract":"<p><p>Functional magnetic resonance imaging (fMRI) data are often used to inform individual differences in cognitive, behavioral, and psychiatric phenotypes. These so-called \"brain-behavior\" association studies come in many flavors and are increasingly the focus of investigations utilizing large population neuroscience datasets. Still, many open questions surrounding the utility of task and resting state fMRI for modelling brain-behavior relationships remain, including the feasibility of conducting these investigations in developmental cohorts. With the growing availability of large neurodevelopmental datasets such as that provided by the Adolescent Brain Cognitive Development (ABCD) Study, we are now able to conduct well-powered analyses using large samples of longitudinal neuroimaging data collected from diverse populations of youth. Here we provide a high-level review of current controversies and challenges in this growing subfield of neuroscience, highlighting examples where task fMRI data and resting state fMRI data - either in isolation or combined - have yielded significant insights into brain-behavior associations. Challenges include issues related to measurement noise, appropriate estimation of effect sizes, and limits to generalizability due to insufficient diversity of samples. Innovative solutions involving advanced MRI data acquisition protocols, application of multivariate analysis methods, and more robust consideration of phenotypic complexity are reviewed. We propose that additional future directions for developmental cognitive neuroscience should include more reliable behavioral measures, multimodal neuroimaging brain-behavior studies, and greater consideration of environmental and other contextual influences on brain-behavior associations.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}