Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia
Abstract The striatum, a core brain structure relevant for schizophrenia, exhibits heterogeneous volumetric changes in this illness. Due to this heterogeneity, its role in the risk of developing schizophrenia following exposure to environmental stress remains poorly understood. Using the putamen (a...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03237-2 |
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| author | Xiaoqian Ma Nana Feng Lena Palaniyappan Luolong Cao Zixin Gu Jujiao Kang Liu Yuan Lijun Ouyang Yujue Wang Chunwang Li Ke Jin Xiaogang Chen Jianfeng Feng Ying He Qiang Luo |
| author_facet | Xiaoqian Ma Nana Feng Lena Palaniyappan Luolong Cao Zixin Gu Jujiao Kang Liu Yuan Lijun Ouyang Yujue Wang Chunwang Li Ke Jin Xiaogang Chen Jianfeng Feng Ying He Qiang Luo |
| author_sort | Xiaoqian Ma |
| collection | DOAJ |
| description | Abstract The striatum, a core brain structure relevant for schizophrenia, exhibits heterogeneous volumetric changes in this illness. Due to this heterogeneity, its role in the risk of developing schizophrenia following exposure to environmental stress remains poorly understood. Using the putamen (a subnucleus of the striatum) as an indicator for convergent genetic risk of schizophrenia, 63 unaffected first-degree relatives of patients (22.08 ± 4.80 years) with schizophrenia (UFR-SZ) were stratified into two groups. Compared with healthy controls (HC; n = 59), voxel-based and brain-wide volumetric changes and their associations with stressful life events (SLE) were tested. These stratified associations were validated using two large population-based cohorts (the ABCD study; n = 1680, 11.92 ± 0.62 years; and UK Biobank, n = 20547, 55.38 ± 7.43 years). Transcriptomic analysis of brain tissues was used to identify the biological processes associated with the brain mediation effects on the SLE-psychosis relationship. The stratified UFR-SZ subgroup with smaller right putamen had a smaller volume in the left caudate when compared to HC; this caudate volume was associated with both a higher level of SLE and more psychotic symptoms. This caudate-SLE association was replicated in two independent large-scale cohorts, when individuals were stratified by both a higher polygenic burden for schizophrenia and smaller right putamen. In UFR-SZ, the caudate cluster mediated the relationship between SLE and more psychotic symptoms. This mediation was associated with the genes enriched in both glutamatergic synapses and response to oxidative stress. The stratified association between the striatum and stress highlights the differential vulnerability to stress, contributing to the complexity of the gene-by-environment etiology of schizophrenia. |
| format | Article |
| id | doaj-art-d99826d8eb4241809b612d24d6cb32dd |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-d99826d8eb4241809b612d24d6cb32dd2025-01-26T12:53:44ZengNature Publishing GroupTranslational Psychiatry2158-31882025-01-011511910.1038/s41398-025-03237-2Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophreniaXiaoqian Ma0Nana Feng1Lena Palaniyappan2Luolong Cao3Zixin Gu4Jujiao Kang5Liu Yuan6Lijun Ouyang7Yujue Wang8Chunwang Li9Ke Jin10Xiaogang Chen11Jianfeng Feng12Ying He13Qiang Luo14Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityDouglas Mental Health University Institute, Department of Psychiatry, McGill UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityDepartment of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityDepartment of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityDepartment of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityDepartment of Radiology, Hunan Children’s HospitalDepartment of Radiology, Hunan Children’s HospitalDepartment of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityDepartment of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South UniversityNational Clinical Research Center for Aging and Medicine at Huashan Hospital, MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan UniversityAbstract The striatum, a core brain structure relevant for schizophrenia, exhibits heterogeneous volumetric changes in this illness. Due to this heterogeneity, its role in the risk of developing schizophrenia following exposure to environmental stress remains poorly understood. Using the putamen (a subnucleus of the striatum) as an indicator for convergent genetic risk of schizophrenia, 63 unaffected first-degree relatives of patients (22.08 ± 4.80 years) with schizophrenia (UFR-SZ) were stratified into two groups. Compared with healthy controls (HC; n = 59), voxel-based and brain-wide volumetric changes and their associations with stressful life events (SLE) were tested. These stratified associations were validated using two large population-based cohorts (the ABCD study; n = 1680, 11.92 ± 0.62 years; and UK Biobank, n = 20547, 55.38 ± 7.43 years). Transcriptomic analysis of brain tissues was used to identify the biological processes associated with the brain mediation effects on the SLE-psychosis relationship. The stratified UFR-SZ subgroup with smaller right putamen had a smaller volume in the left caudate when compared to HC; this caudate volume was associated with both a higher level of SLE and more psychotic symptoms. This caudate-SLE association was replicated in two independent large-scale cohorts, when individuals were stratified by both a higher polygenic burden for schizophrenia and smaller right putamen. In UFR-SZ, the caudate cluster mediated the relationship between SLE and more psychotic symptoms. This mediation was associated with the genes enriched in both glutamatergic synapses and response to oxidative stress. The stratified association between the striatum and stress highlights the differential vulnerability to stress, contributing to the complexity of the gene-by-environment etiology of schizophrenia.https://doi.org/10.1038/s41398-025-03237-2 |
| spellingShingle | Xiaoqian Ma Nana Feng Lena Palaniyappan Luolong Cao Zixin Gu Jujiao Kang Liu Yuan Lijun Ouyang Yujue Wang Chunwang Li Ke Jin Xiaogang Chen Jianfeng Feng Ying He Qiang Luo Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia Translational Psychiatry |
| title | Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| title_full | Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| title_fullStr | Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| title_full_unstemmed | Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| title_short | Neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| title_sort | neuroimaging stratification reveals the striatal vulnerability to stress as a risk for schizophrenia |
| url | https://doi.org/10.1038/s41398-025-03237-2 |
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