Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia
Abstract Background Intermediate phenotypes, such as characteristic neuroimaging patterns, offer unique insights into the genetic and stress-related underpinnings of neuropsychiatric disorders like depression. This study aimed to identify neuroimaging intermediate phenotypes associated with depressi...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-025-03850-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585672055062528 |
|---|---|
| author | Huiling Guo Yao Xiao Shuai Dong Jingyu Yang Pengfei Zhao Tongtong Zhao Aoling Cai Lili Tang Juan Liu Hui Wang Ruifang Hua Rongxun Liu Yange Wei Dandan Sun Zhongchun Liu Mingrui Xia Yong He Yankun Wu Tianmei Si Fay Y. Womer Fuqiang Xu Yanqing Tang Jie Wang Weixiong Zhang Xizhe Zhang Fei Wang |
| author_facet | Huiling Guo Yao Xiao Shuai Dong Jingyu Yang Pengfei Zhao Tongtong Zhao Aoling Cai Lili Tang Juan Liu Hui Wang Ruifang Hua Rongxun Liu Yange Wei Dandan Sun Zhongchun Liu Mingrui Xia Yong He Yankun Wu Tianmei Si Fay Y. Womer Fuqiang Xu Yanqing Tang Jie Wang Weixiong Zhang Xizhe Zhang Fei Wang |
| author_sort | Huiling Guo |
| collection | DOAJ |
| description | Abstract Background Intermediate phenotypes, such as characteristic neuroimaging patterns, offer unique insights into the genetic and stress-related underpinnings of neuropsychiatric disorders like depression. This study aimed to identify neuroimaging intermediate phenotypes associated with depression, bridging etiological factors to behavioral manifestations and connecting insights from animal models to diverse clinical populations. Methods We analyzed datasets from both rodents and humans. The rodent studies included a genetic model (P11 knockout) and an environmental stress model (chronic unpredictable mild stress), while the human data comprised 748 participants from three cohorts. Using the amplitude of low-frequency fluctuations, we identified neuroimaging patterns in rodent models. We then applied a machine-learning approach to cluster neuroimaging subtypes of depression. To assess the genetic predispositions and stress-related changes associated with these subtypes, we analyzed genotype and metabolite data. Linear regression was employed to determine which neuroimaging features predicted core depression symptoms across species. Results The genetic and environmental stress models exhibited distinct neuroimaging patterns in subcortical and sensorimotor regions. Consistent patterns emerged in two neuroimaging subtypes identified across three independent depressed cohorts. The subtype resembling P11 knockout demonstrated higher genetic susceptibility, with enriched expression of risk genes in brain tissues and abnormal metabolites linked to tryptophan metabolism. In contrast, the stress animal-like subtype did not show changes in genetic risk scores but exhibited enriched risk gene expression in somatic and endocrine tissues, along with mitochondrial dysfunction in the antioxidant stress system. Notably, these distinct subcortical-sensorimotor neuroimaging patterns predicted anhedonia, a core symptom of depression, in both rodent models and depressed subtypes. Conclusions This cross-species validation suggests that these neuroimaging patterns may serve as robust intermediate phenotypes, linking etiology to anhedonia and facilitating the translation of findings from animal models to humans with depression and other psychiatric disorders. |
| format | Article |
| id | doaj-art-d7c5b56eef0e4957b537ab4a94e7290f |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj-art-d7c5b56eef0e4957b537ab4a94e7290f2025-01-26T12:37:11ZengBMCBMC Medicine1741-70152025-01-0123111610.1186/s12916-025-03850-4Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedoniaHuiling Guo0Yao Xiao1Shuai Dong2Jingyu Yang3Pengfei Zhao4Tongtong Zhao5Aoling Cai6Lili Tang7Juan Liu8Hui Wang9Ruifang Hua10Rongxun Liu11Yange Wei12Dandan Sun13Zhongchun Liu14Mingrui Xia15Yong He16Yankun Wu17Tianmei Si18Fay Y. Womer19Fuqiang Xu20Yanqing Tang21Jie Wang22Weixiong Zhang23Xizhe Zhang24Fei Wang25Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityHenan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical UniversityHenan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityDepartment of Cardiac Function, The People’s Hospital of China Medical University and the People’s Hospital of Liaoning ProvinceDepartment of Psychiatry, Renmin Hospital of Wuhan UniversityState Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal UniversityState Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal UniversityPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking UniversityPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking UniversityDepartment of Psychiatry and Behavioral Sciences, Vanderbilt University Medical CenterKey Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for OptoelectronicsDepartment of Psychiatry, Shengjing Hospital of China Medical UniversitySongjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of MedicineDepartment of Health Technology and Informatics, Department of Computing, The Hong Kong Polytechnic UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityEarly Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityAbstract Background Intermediate phenotypes, such as characteristic neuroimaging patterns, offer unique insights into the genetic and stress-related underpinnings of neuropsychiatric disorders like depression. This study aimed to identify neuroimaging intermediate phenotypes associated with depression, bridging etiological factors to behavioral manifestations and connecting insights from animal models to diverse clinical populations. Methods We analyzed datasets from both rodents and humans. The rodent studies included a genetic model (P11 knockout) and an environmental stress model (chronic unpredictable mild stress), while the human data comprised 748 participants from three cohorts. Using the amplitude of low-frequency fluctuations, we identified neuroimaging patterns in rodent models. We then applied a machine-learning approach to cluster neuroimaging subtypes of depression. To assess the genetic predispositions and stress-related changes associated with these subtypes, we analyzed genotype and metabolite data. Linear regression was employed to determine which neuroimaging features predicted core depression symptoms across species. Results The genetic and environmental stress models exhibited distinct neuroimaging patterns in subcortical and sensorimotor regions. Consistent patterns emerged in two neuroimaging subtypes identified across three independent depressed cohorts. The subtype resembling P11 knockout demonstrated higher genetic susceptibility, with enriched expression of risk genes in brain tissues and abnormal metabolites linked to tryptophan metabolism. In contrast, the stress animal-like subtype did not show changes in genetic risk scores but exhibited enriched risk gene expression in somatic and endocrine tissues, along with mitochondrial dysfunction in the antioxidant stress system. Notably, these distinct subcortical-sensorimotor neuroimaging patterns predicted anhedonia, a core symptom of depression, in both rodent models and depressed subtypes. Conclusions This cross-species validation suggests that these neuroimaging patterns may serve as robust intermediate phenotypes, linking etiology to anhedonia and facilitating the translation of findings from animal models to humans with depression and other psychiatric disorders.https://doi.org/10.1186/s12916-025-03850-4DepressionSubtypesAnimalNeuroimagingIntermediate phenotypesCross-species |
| spellingShingle | Huiling Guo Yao Xiao Shuai Dong Jingyu Yang Pengfei Zhao Tongtong Zhao Aoling Cai Lili Tang Juan Liu Hui Wang Ruifang Hua Rongxun Liu Yange Wei Dandan Sun Zhongchun Liu Mingrui Xia Yong He Yankun Wu Tianmei Si Fay Y. Womer Fuqiang Xu Yanqing Tang Jie Wang Weixiong Zhang Xizhe Zhang Fei Wang Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia BMC Medicine Depression Subtypes Animal Neuroimaging Intermediate phenotypes Cross-species |
| title | Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| title_full | Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| title_fullStr | Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| title_full_unstemmed | Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| title_short | Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| title_sort | bridging animal models and humans neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia |
| topic | Depression Subtypes Animal Neuroimaging Intermediate phenotypes Cross-species |
| url | https://doi.org/10.1186/s12916-025-03850-4 |
| work_keys_str_mv | AT huilingguo bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT yaoxiao bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT shuaidong bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT jingyuyang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT pengfeizhao bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT tongtongzhao bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT aolingcai bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT lilitang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT juanliu bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT huiwang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT ruifanghua bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT rongxunliu bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT yangewei bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT dandansun bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT zhongchunliu bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT mingruixia bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT yonghe bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT yankunwu bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT tianmeisi bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT fayywomer bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT fuqiangxu bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT yanqingtang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT jiewang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT weixiongzhang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT xizhezhang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia AT feiwang bridginganimalmodelsandhumansneuroimagingasintermediatephenotypeslinkinggeneticorstressfactorstoanhedonia |