Translational Psychiatry最新文献

{"title":"Associations of clinical biomarker-based biological aging with suicide attempts and suicidal ideation: evidence from 124,529 UK Biobank participants.","authors":"Wei Hu, Zhenzhen Shen, Ge Tian, Baopeng Liu, Cunxian Jia","doi":"10.1038/s41398-025-03412-5","DOIUrl":"https://doi.org/10.1038/s41398-025-03412-5","url":null,"abstract":"<p><p>Biological aging has been linked to multiple psychological disorders, yet its extrapolation to suicide remains absent. We aimed to examine the associations of biological aging with suicidal ideation (SI) and suicide attempt (SA) and to explore possible moderators of the associations. A total of 124,529 middle and older participants from the UK Biobank were included. Phenotypic age (PhenoAge) indicating biological aging was calculated based on chronological age and nine clinical biomarkers. The residuals of PhenoAge regressed on chronological age were utilized to quantify biological aging, termed PhenoAge acceleration (PAA). Approximately one-third of baseline participants completed mental health follow-up questionnaires including suicide-related information. Multivariate logistic regression models were performed to estimate the associations. 2718 (2.2%) SA and 5207 (4.4%) SI cases were documented. Compared with participants in the lowest quartile of PAA, those in the highest quartile had a 21.8% [odds ratio (OR) = 1.218; 95% confidence interval (CI): 1.087-1.198) and 12.5% (OR = 1.125, 95% CI: 1.035-1.224) higher odds of SA and SI, respectively. Biologically older participants (PAA > 0) were more likely to report SA (OR = 1.104, 95% CI: 1.018-1.198) and SI (OR = 1.064, 95% CI: 1.003-1.129). Gender, age, socioeconomic status (SES), physical activity, and somatic and psychiatric disorders could modify the associations (P for interaction <0.05). Our findings indicated that PAA-measured aging might be positively associated with SA/SI. Interventions aimed at slowing aging might contribute to suicide prevention, especially among males, young adults, low SES, the physically inactive, and vulnerable populations.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"204"},"PeriodicalIF":5.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326972","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":"Chronic postoperative pain induces contextual fear extinction dysfunction through hippocampal NMDAR/BDNF/TrkB signaling pathway in mice.","authors":"Jiawei Zhang, Xiaoting Zheng, Gaoyan Zhang, Zhikun Cheng, Yinuo Liu, Lei Zhang, Jiqian Zhang, Xuesheng Liu, Zhilai Yang","doi":"10.1038/s41398-025-03417-0","DOIUrl":"https://doi.org/10.1038/s41398-025-03417-0","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is a common disorder in clinical practice, characterized by various manifestations, with fear extinction dysfunction being a typical one. Postoperative persistent pain, a form of chronic pain following surgical procedures, significantly affects patients' quality of life. Clinical studies have demonstrated the comorbidity between chronic pain and PTSD; however, the molecular mechanisms underlying this comorbidity remain unclear. Researches have shown that brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate glutamate receptors (NMDARs) are crucial in fear extinction dysfunction. Thus, we established a skin/muscle incision and retraction (SMIR) mice model to explore the roles of hippocampal NMDARs and BDNF signaling pathways in fear extinction following postoperative persistent pain. We found that SMIR mice exhibited contextual fear extinction dysfunction, potentially caused by a down-regulated NMDARs/ERK/CREB/BDNF signaling pathway and impaired synaptic plasticity in the hippocampus. Hippocampal injection of the NMDARs agonist NMDA promoted extinction learning and retrieval of extinction memory, activating the NMDARs/ERK/CREB/BDNF signaling pathway, and restoring lost dendritic spines. Simultaneous hippocampal administration of NMDA and the TrkB inhibitor ANA-12 promoted the learning process of fear extinction without enhancing the retrieval of extinction memory, while re-inducing dendritic spine loss. In summary, we conclude that postoperative persistent pain impairs synaptic plasticity by downregulating the NMDARs/ERK/CREB/BDNF signaling pathway, thereby inducing contextual fear extinction dysfunction. These findings may partially explain the mechanisms underlying the comorbidity between chronic pain and PTSD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"203"},"PeriodicalIF":5.8,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318021","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":"The molecular mechanisms through which psilocybin prevents suicide: evidence from network pharmacology and molecular docking analyses.","authors":"Ying Zhang, Lei Yang, Qiuyu Zhang, Chao Li, Fuqiang Mao, Chuanjun Zhuo","doi":"10.1038/s41398-025-03410-7","DOIUrl":"10.1038/s41398-025-03410-7","url":null,"abstract":"<p><p>Psilocybin is among the most extensively studied psychedelics, with previous research suggesting its potential therapeutic role in suicide prevention. However, the precise mechanisms through which psilocybin may aid in suicide prevention remain unclear. This study thus employed network pharmacology and molecular docking tools to explore the mechanisms by which psilocybin may contribute to suicide prevention. Relevant drug- and disease-related targets were identified. Overlapping drug- and disease-related targets were extracted from the bioinformatics platform and imported into the STRING database to construct a protein-protein interaction (PPI) network. Key targets were selected based on topological parameters derived from network analyses conducted using Cytoscape 3.10.1. These key targets were further analyzed using GO and KEGG enrichment approaches conducted with the DAVID tool. A drug-disease-target-pathway network was subsequently constructed in Cytoscape 3.10.1. Finally, molecular docking analyses were performed to assess psilocybin's potential to interact with key targets using AutoDock Vina and the PyMOL software. A total of 46 potential targets associated with psilocybin and relevant to suicide treatment were identified, of which 13 were imported into the DAVID tool for enrichment analyses. Network analyses identified four targets-HTR2A, HTR2C, HTR7, and PRKACA-that may serve as therapeutic targets for psilocybin in suicide prevention. Enrichment analysis outcomes suggested that psilocybin may prevent suicide by modulating the serotonergic synapse and calcium signaling pathways. Molecular docking analyses revealed that HTR2A, HTR2C, HTR7, and PRKACA strongly bind to psilocybin. This study provides insights into the molecular mechanisms underlying the potential role of psilocybin in suicide prevention, offering a novel basis for further research.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"202"},"PeriodicalIF":5.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of behavioural and neurochemical effects of psilocybin in mice subjected to chronic unpredictable mild stress.","authors":"Ines Erkizia-Santamaría, Igor Horrillo, Nerea Martínez-Álvarez, Daniel Pérez-Martínez, Guadalupe Rivero, Amaia M Erdozain, J Javier Meana, Jorge E Ortega","doi":"10.1038/s41398-025-03421-4","DOIUrl":"10.1038/s41398-025-03421-4","url":null,"abstract":"<p><p>Depression and anxiety are disabling and high incidence mental disorders characterized by phenotypic heterogeneity. Currently available treatments show severe limitations. Thus, there is an urgent need for effective treatments in this population. In the search for novel rapid-acting antidepressants, the psychedelic psilocybin has emerged as a promising therapy in several clinical trials. However, its antidepressant mechanism of action is still not well understood. The aim of the present study was to evaluate the therapeutic potential of psilocybin in ameliorating the adverse behavioural and neurochemical consequences of chronic stress. To this end, a chronic unpredictable mild stress (CUMS) animal model was used, and psilocybin treatment was administered (two doses of 1 mg/kg, i.p., administered 7 days apart). Psilocybin reversed impairments in anhedonia and behavioural despair dimensions of depressive phenotype but not in apathy-related behaviour. Psilocybin administration was also able to exert an anxiolytic-like effect on treated animals. Physiological alterations caused by stress, indicative of a hyperactive hypothalamic-pituitary-adrenal axis (HPA), were not reversed by psilocybin. When neuroplasticity-related proteins were assessed in cerebral cortex, brain-derived neurotrophic factor (BDNF) was found to be decreased in stressed animals, and treatment did not reverse such impairment. Psilocybin administration increased the expression and function of serotonin-2A-receptor (5HT2AR) in brain cortex of control and CUMS groups. Furthermore, psilocybin treatment caused a selective increase in the expression of glucocorticoid-receptor (GR) in brain cortex of CUMS mice. In conclusion, psilocybin was able to rescue impairments in the depressive phenotype, and to induce anxiolytic-like effects. Furthermore, an enhancement in sensitivity to psilocybin-induced HTR was observed following a booster dose. Altogether, this work provides new knowledge on the putative benefit/risk actions of psilocybin and contributes to the understanding of the therapeutic mechanism of action of psychedelics.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"201"},"PeriodicalIF":5.8,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multilevel brain functional connectivity and task-based representations explaining heterogeneity in major depressive disorder.","authors":"Qi Liu, Xinqi Zhou, Chunmei Lan, Xiaolei Xu, Yuanshu Chen, Taolin Chen, Jinhui Wang, Bo Zhou, Dezhong Yao, Keith M Kendrick, Benjamin Becker, Weihua Zhao","doi":"10.1038/s41398-025-03413-4","DOIUrl":"10.1038/s41398-025-03413-4","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a devastating mental disorder characterized by considerable clinical and biological heterogeneity. While comparable clinical symptoms may represent a common pathological endpoint, it is conceivable that distinct neurophysiological mechanisms underlie their manifestation. In this study, both static and model-based dynamic functional connectivity were employed as predictive variables in the normative model to map multilevel functional developmental trajectories and determined clusters of distinguishable MDD subgroups in a large multi-site resting fMRI dataset of 2428 participants (healthy controls: N = 1128; MDD: N = 1300). An independent cohort of 72 participants (healthy controls: N = 35; MDD: N = 37) with both resting fMRI and task-based fMRI data was utilized to validate the identified MDD subtypes and explore subtype-specific task-based neural representations. Our findings indicated brain-wide, interpatient heterogeneous multilevel brain functional deviations in MDD. We identified two distinct and reproducible MDD subtypes, exhibiting comparable severity of clinical symptoms but opposing patterns of multilevel functional deviations. Specifically, MDD subtype 1 displayed positive deviations in the frontoparietal and default mode networks, coupled with negative deviations in the occipital and sensorimotor networks. Conversely, MDD subtype 2 exhibited a significantly contrasting deviation pattern. Additionally, we found that these two identified MDD subtypes exhibited different neural representations during empathic processing, while the subtypes did not differ during implicit face processing. These findings underscore the neurobiological complexity of MDD and highlights the need for a multifaceted approach to diagnosis and treatment that can be tailored specifically to individual subtypes, facilitating personalized and more effective interventions for individuals with MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"199"},"PeriodicalIF":5.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration.","authors":"Tom Ben-Tal, Ilana Pogodin, Alexander Botvinnik, Tzuri Lifschytz, Uriel Heresco-Levy, Bernard Lerer","doi":"10.1038/s41398-025-03428-x","DOIUrl":"10.1038/s41398-025-03428-x","url":null,"abstract":"<p><p>The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR-a surrogate measure for hallucinogenic effects-which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"200"},"PeriodicalIF":5.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBT treatment delivery formats for generalized anxiety disorder: a systematic review and network meta-analysis of randomized controlled trials.","authors":"Shiyu Liu, Hongqi Xiao, Yingxu Duan, Lixin Shi, Ping Wang, Lingxiao Cao, Hailong Li, Xiaoqi Huang, Changjian Qiu","doi":"10.1038/s41398-025-03414-3","DOIUrl":"10.1038/s41398-025-03414-3","url":null,"abstract":"<p><strong>Objectives: </strong>To assess the comparative efficacy and acceptability of different delivery formats of cognitive behavior therapy (CBT) in treating generalized anxiety disorder (GAD).</p><p><strong>Methods: </strong>We searched MEDLINE, Embase, PsycINFO, and the Web of Science from database inception to September, 2023, to identify randomized clinical trials (RCTs) of CBT for patients with GAD. Pairwise and network meta-analyses were conducted using a random-effects model.</p><p><strong>Results: </strong>Finally, 52 trials that randomized 4361 patients (mean age 43 years; 69.7% women) with generalized anxiety disorder met the inclusion criteria. The most studied treatment comparisons were individual and remote CBT versus waiting list. The quality of the evidence was typically of low or unclear risk of bias (39 out of 52 trials, 75%). The network meta-analysis including 30 studies showed that individual CBT was superior to remote CBT (SMD 0.96; 95% Cl 0.13-1.79), treatment as usual (SMD 1.12; 95% Cl 0.24-2.00) and waiting list (SMD 1.62; 95% Cl 1.03-2.22) in relieving anxiety symptoms of GAD. Group CBT (SMD 1.65; 95% Cl 0.47-2.84) was more efficacious than waiting list. Remote CBT was not superior to treatment as usual or waiting list. In terms of acceptability CBT delivery formats did not differ significantly from each other.</p><p><strong>Conclusions: </strong>Our findings provide evidence for the consideration of group treatment formats as alternative to individual CBT in relieving anxiety symptoms in patients with GAD, but remote CBT may be less effective.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"197"},"PeriodicalIF":5.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concentration-dependent effect of delta-9-tetrahydrocannabinol on epigenetic DNA modifiers in human peripheral blood mononuclear cells.","authors":"Kerda Pulk, Kelli Somelar-Duracz, Mikk Rooden, Kaili Anier, Anti Kalda","doi":"10.1038/s41398-025-03419-y","DOIUrl":"10.1038/s41398-025-03419-y","url":null,"abstract":"<p><p>Cannabis is among the most used illicit substances in the world, and approximately 10% of regular cannabis users are estimated to be susceptible to developing cannabis use disorder (CUD). We examined the effect of different concentrations of delta-9-tetrahydrocannabinol (THC) on the epigenetic DNA modifiers DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs); cannabinoid CB1 and CB2 receptors; and the cytokines IL-1β, IL-6, IL-10, and TNF-α. We used two in vitro study designs on human peripheral blood mononuclear cells (PBMCs) collected from healthy donors: (a) repeated THC incubations and (b) repeated THC incubations followed by an \"abstinence\" period and a THC challenge incubation. We observed no significant effects on DNMTs and TETs mRNA levels, enzymatic activity, or CB1 and CB2 mRNA levels at an average THC concentration (50 ng/ml, n = 8 donors). However, repeated incubations at a high THC concentration (200 ng/ml, n = 16 donors) significantly downregulated DNMTs and upregulated TETs, CB1, and CB2 mRNA levels. Both THC concentrations upregulated the gene expression of IL-1β, IL-6, and IL-10, but had no effect on TNF-α gene expression. At the genome-wide level, repeated THC incubations resulted in a significant number of differentially hydroxymethylated genes being hyperhydroxymethylated. An additional THC challenge shifted the hyperhydroxymethylated state to hypohydroxymethylation. The genes with the strongest associations with THC exposure were found to be functionally significant for various signaling pathways. These findings suggest that repeated incubations with high concentrations of THC may affect the expression of genes critical for the development of CUD through aberrant demethylation.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"198"},"PeriodicalIF":5.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A large-scale multimodal investigation of the interplay between the serotonergic system and emotion processing.","authors":"Manfred Klöbl, Matej Murgaš, Murray Bruce Reed, Leo Robert Silberbauer, Annette M Hartmann, Godber Mathis Godbersen, Gregor Gryglewski, Lukas Nics, Andreas Hahn, Dan Rujescu, Marcus Hacker, Rupert Lanzenberger","doi":"10.1038/s41398-025-03407-2","DOIUrl":"10.1038/s41398-025-03407-2","url":null,"abstract":"<p><p>Considering the complexity of serotonergic influence on emotions, we conducted a comprehensive investigation of the interplay between emotion processing and the serotonergic system using simultaneous functional and molecular neuroimaging during pharmacological challenge while disentangling the effects of serotonin transporter (SERT) binding, genotype, and diagnosis of major depressive disorder (MDD). Herein, 153 subjects (44 with MDD) performed a facial emotion processing task during functional magnetic resonance imaging (fMRI) before and after an acute intravenous application of 8 mg citalopram or placebo. Patients with MDD were assessed again after at least three months of antidepressant treatment. Citalopram administration resulted in a reduced fMRI activation in regions involved in fear processing, including the anterior cingulate cortex (ACC), when viewing fearful faces contrasted against happy or neutral faces. ACC activation correlated negatively with striatal/thalamic SERT availability across drug conditions as measured by [11 C]DASB positron emission tomography. Across groups, citalopram-induced changes in ACC activation correlated with emotional attribution, indicating stronger reductions for subjects with higher self- versus other- attribution. Moreover, striatal SERT availability mediated the influence of the number of 5-HTTLPR/rs25531 L_A alleles on ACC activation under placebo. Patients with MDD exhibited increased activations in the intraparietal and superior frontal sulcus in response to fearful versus happy faces at baseline, and along the parieto-occipital/calcarine fissure after treatment. We interpret our findings on multiple levels of the serotonergic-emotional interaction within the context of enhanced passive coping and acute anxiolytic effects of citalopram following potential changes in serotonin or SERT availability.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"196"},"PeriodicalIF":5.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12159172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring individual differences in fear extinction in male and female mice: insights from HPA axis, microbiota, and transcriptomics.","authors":"Marc Ten-Blanco, María Ponce-Renilla, Inmaculada Pereda-Pérez, Cristina Izquierdo-Luengo, Carlo Bressa, Olga Zafra, Rosa María Tolón, Fernando Berrendero","doi":"10.1038/s41398-025-03400-9","DOIUrl":"10.1038/s41398-025-03400-9","url":null,"abstract":"<p><p>Exposure to traumatic life events may compromise physical and mental health of specific subjects. While some individuals extinguish fear appropriately, others exhibit an inefficient and persistent fear response, with remarkable differences between sexes. Understanding the heterogeneity in fear extinction responses is essential for elucidating the underlying mechanisms of fear-related disorders. We used a multidisciplinary approach analyzing the hypothalamic-pituitary-adrenal (HPA) axis tone, the microbiota composition, and the transcriptome of the amygdala (primary brain region involved in fear regulation) in adult male and female mice that were exposed to the Pavlovian fear conditioning and extinction paradigm. This model allowed us to stratify the mice population into two extreme phenotypic subgroups (resilient and susceptible), based on their individual fear extinction behavior. Characterization of some components of the HPA axis revealed strong disturbances in vulnerable males (e.g., increased hypothalamic CRF mRNA and corticosterone plasma levels), whereas softer changes were found in female animals. Several bacterial groups such as the genera Parvibacter, Alloprevotella and Limosilactobacillus and the family Christensenellaceae were enriched in the microbiota of resilient males, as well as relevant bacterial taxa enrichment was also observed in resilient (genus Muribaculum) and susceptible (family Eggerthellaceae) female mice. We also identified clear differences in the transcriptomic profile of the amygdala (31 differentially expressed genes) in male animals. These findings underscore the intricate involvement of multiple factors shaping the inter-individual variability of fear extinction response in a sex-dependent manner, thus paving the way for new potential targets for fear-related disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"195"},"PeriodicalIF":5.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}