Translational Psychiatry最新文献

{"title":"Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum.","authors":"Junhao Wen, Zhijian Yang, Ilya M Nasrallah, Yuhan Cui, Guray Erus, Dhivya Srinivasan, Ahmed Abdulkadir, Elizabeth Mamourian, Gyujoon Hwang, Ashish Singh, Mark Bergman, Jingxuan Bao, Erdem Varol, Zhen Zhou, Aleix Boquet-Pujadas, Jiong Chen, Arthur W Toga, Andrew J Saykin, Timothy J Hohman, Paul M Thompson, Sylvia Villeneuve, Randy Gollub, Aristeidis Sotiras, Katharina Wittfeld, Hans J Grabe, Duygu Tosun, Murat Bilgel, Yang An, Daniel S Marcus, Pamela LaMontagne, Tammie L Benzinger, Susan R Heckbert, Thomas R Austin, Lenore J Launer, Mark Espeland, Colin L Masters, Paul Maruff, Jurgen Fripp, Sterling C Johnson, John C Morris, Marilyn S Albert, R Nick Bryan, Susan M Resnick, Luigi Ferrucci, Yong Fan, Mohamad Habes, David Wolk, Li Shen, Haochang Shou, Christos Davatzikos","doi":"10.1038/s41398-024-03121-5","DOIUrl":"10.1038/s41398-024-03121-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the \"diffuse-AD\" (R1) dimension shows widespread brain atrophy, and the \"MTL-AD\" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were \"druggable genes\" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378342","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":"Probing the oral-brain connection: oral microbiome patterns in a large community cohort with anxiety, depression, and trauma symptoms, and periodontal outcomes.","authors":"Stefanie Malan-Müller, Rebeca Vidal, Esther O'Shea, Eduardo Montero, Elena Figuero, Iñaki Zorrilla, Javier de Diego-Adeliño, Marta Cano, Maria Paz García-Portilla, Ana González-Pinto, Juan C Leza","doi":"10.1038/s41398-024-03122-4","DOIUrl":"10.1038/s41398-024-03122-4","url":null,"abstract":"<p><p>The role of the oral microbiome in mental health has recently been appreciated within the proposed oral-brain axis. This study examined the structure and composition of the salivary microbiome in a large-scale population-based cohort of individuals reporting mental health symptoms (n = 306) compared to mentally healthy controls (n = 164) using 16S rRNA sequencing. Mental health symptoms were evaluated using validated questionnaires and included depression, anxiety, and posttraumatic stress disorder (PTSD), with accompanying periodontal outcomes. Participants also indicated current or previous diagnoses of anxiety, depression, periodontitis, and gingivitis. Mental and periodontal health variables influenced the overall composition of the oral microbiome. PTSD symptoms correlated with a lower clr-transformed relative abundance of Haemophilus sputorum and a higher clr-transformed relative abundance of Prevotella histicola. The clr-transformed relative abundance of P. histicola was also positively associated with depressive scores and negatively associated with psychological quality of life. Anxiety disorder diagnosis was associated with a lower clr-transformed relative abundance of Neisseria elongate and a higher clr-transformed relative abundance of Oribacterium asaccharolyticum. A higher clr-transformed relative abundance of Shuttleworthia and lower clr-transformed relative abundance of Capnocytophaga were evident in those who reported a clinical periodontitis diagnosis. Higher Eggerthia and lower Haemophilus parainfluenzae clr-transformed relative abundances were associated with reported clinical periodontitis diagnoses and psychotherapeutic efficacy. Functional prediction analysis revealed a potential role for tryptophan metabolism/degradation in the oral-brain axis, which was confirmed by lower plasma serotonin levels across symptomatic groups. This study sheds light on the intricate interplay between oral microbiota, periodontal and mental health outcomes, and a potential role for tryptophan metabolism in the proposed oral-brain axis, emphasizing the need for further exploration to pave the way for novel therapeutic interventions and predicting therapeutic response.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378343","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":"Basolateral amygdala parvalbumin and cholecystokinin-expressing GABAergic neurons modulate depressive and anxiety-like behaviors.","authors":"Muhammad Asim, Huajie Wang, Abdul Waris, Jufang He","doi":"10.1038/s41398-024-03135-z","DOIUrl":"10.1038/s41398-024-03135-z","url":null,"abstract":"<p><p>The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLA^GABA) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLA^GABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLA^GABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLA^PV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLA^PV neurons alleviated depressive behaviors, and activation of BLA^CCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLA^PV neurons play a critical role in regulating depressive-like behaviors, and that BLA^CCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378341","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":"Deciphering autism heterogeneity: a molecular stratification approach in four mouse models.","authors":"Caroline Gora, Ana Dudas, Océane Vaugrente, Lucile Drobecq, Emmanuel Pecnard, Gaëlle Lefort, Lucie P Pellissier","doi":"10.1038/s41398-024-03113-5","DOIUrl":"10.1038/s41398-024-03113-5","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376092","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":"Cortical kappa opioid receptors integrate negative affect and sleep disturbance.","authors":"Robson C Lillo Vizin, Hisakatsu Ito, Caroline M Kopruszinski, Megumi Ikegami, Daigo Ikegami, Xu Yue, Edita Navratilova, Aubin Moutal, Stephen L Cowen, Frank Porreca","doi":"10.1038/s41398-024-03123-3","DOIUrl":"10.1038/s41398-024-03123-3","url":null,"abstract":"<p><p>Sleep disruption and negative affect are attendant features of many psychiatric and neurological conditions that are often co-morbid including major depressive disorder, generalized anxiety disorder and chronic pain. Whether there is a causal relationship between negative affect and sleep disruption remains unclear. We therefore asked if mechanisms promoting negative affect can disrupt sleep and whether inhibition of pathological negative affect can normalize disrupted sleep. Signaling at the kappa opioid receptor (KOR) elicits dysphoria in humans and aversive conditioning in animals. We tested the possibility that (a) increased KOR signaling in the anterior cingulate cortex (ACC), a brain region associated with negative emotions, would be sufficient to promote both aversiveness and sleep disruption and (b) inhibition of KOR signaling would normalize pathological negative affect and sleep disruption induced by chronic pain. Chemogenetic Gi-mediated inhibition of KOR-expressing ACC neurons produced conditioned place aversion (CPA) as well as sleep fragmentation in naïve mice. CRISPR/Cas9 editing of ACC KOR normalized both the negative affect and sleep disruption elicited by pathological chronic pain while maintaining the physiologically critical sensory features of pain. These findings suggest therapeutic utility of KOR antagonists for treatment of disease conditions that are associated with both negative affect and sleep disturbances.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376091","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":"Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography.","authors":"Tsuyoshi Nishiguchi, Kyosuke Yamanishi, Shivani Patel, Johnny R Malicoat, Nathan James Phuong, Tomoteru Seki, Takaya Ishii, Bun Aoyama, Akiyoshi Shimura, Nipun Gorantla, Takehiko Yamanashi, Masaaki Iwata, Andrew A Pieper, Gen Shinozaki","doi":"10.1038/s41398-024-03130-4","DOIUrl":"10.1038/s41398-024-03130-4","url":null,"abstract":"<p><p>Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366608","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":"Serum cytokines and inflammatory proteins in individuals with heroin use disorder: potential mechanistically based biomarkers for diagnosis.","authors":"Eduardo R Butelman, Yuefeng Huang, Flurin Cathomas, Pierre-Olivier Gaudreault, Panos Roussos, Scott J Russo, Rita Z Goldstein, Nelly Alia-Klein","doi":"10.1038/s41398-024-03119-z","DOIUrl":"10.1038/s41398-024-03119-z","url":null,"abstract":"<p><p>Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in the blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially considered as a multi-target biomarker. We used a validated proximity extension assay for the relative quantification of 92 cytokines and inflammatory proteins in the serum of iHUD on medication-assisted therapy (MAT; n = 21), compared to HC (n = 24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison corrections (p = 0.05). These targets included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, with PC1 scores showing significant group differences (iHUD > HC; p < 0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC = 91.7% (p < 0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, that included select demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, providing a multi-target \"cytokine biomarker score\" for potential diagnostic purposes, and future examination of disease severity.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372956","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":"Oral antioxidant edaravone protects against cognitive deficits induced by chronic hypobaric hypoxia at high altitudes.","authors":"Yuan-Yuan Ma, Xin Li, Zhong-Yuan Yu, Tong Luo, Cheng-Rong Tan, Yu-Di Bai, Gang Xu, Bin-Da Sun, Xian-Le Bu, Yu-Hui Liu, Wang-Sheng Jin, Yu-Qi Gao, Xin-Fu Zhou, Juan Liu, Yan-Jiang Wang","doi":"10.1038/s41398-024-03133-1","DOIUrl":"10.1038/s41398-024-03133-1","url":null,"abstract":"<p><p>Chronic hypobaric hypoxia at high altitudes can impair cognitive functions, especially causing deficits in learning and memory, which require therapeutic intervention. Here, we showed that mice subjected to hypobaric hypoxia (simulating an altitude of 5000 m) for one month experienced significant cognitive impairment, accompanied by increased biomarker levels of oxidative stress in the brain and blood. Oral administration of a novel formulation of edaravone, a free radical scavenger approved for the treatment of ischaemic stroke and amyotrophic lateral sclerosis, significantly alleviated oxidative stress and cognitive impairments caused by chronic hypobaric hypoxia. Furthermore, oral edaravone treatment also mitigated neuroinflammation and restored hippocampal neural stem cell exhaustion. Additionally, periostin (Postn) is vital in the cognitive deficits caused by chronic hypobaric hypoxia and may be a molecular target of edaravone. In conclusion, our results suggest that oxidative stress plays a crucial role in the cognitive deficits caused by chronic hypobaric hypoxia and that oral edaravone is a potential medicine for protecting against cognitive deficits caused by chronic hypobaric hypoxia in high-altitude areas.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372955","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":"Dorsal raphe dopaminergic neurons target CaMKII⁺ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors.","authors":"Wentao Wang, Dan Wang, Di Zhao, Lihong Xu, Shujun Jiang, Yu Zhang, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Dunjiang Liu, Wei Li, Chen Li","doi":"10.1038/s41398-024-03093-6","DOIUrl":"10.1038/s41398-024-03093-6","url":null,"abstract":"<p><p>Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II⁺ (CaMKII⁺⁾ target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRN^DA → dBNST^CaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366609","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":"Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure.","authors":"Lydia M Federmann, Friederike S David, Christiane Jockwitz, Thomas W Mühleisen, Dominique I Pelzer, Markus M Nöthen, Svenja Caspers, Katrin Amunts, Janik Goltermann, Till F M Andlauer, Frederike Stein, Katharina Brosch, Tilo Kircher, Sven Cichon, Udo Dannlowski, Lisa Sindermann, Andreas J Forstner","doi":"10.1038/s41398-024-03098-1","DOIUrl":"10.1038/s41398-024-03098-1","url":null,"abstract":"<p><p>A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366604","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}