• 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, and Fei Wang.
• Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, 264 Guangzhou Street, Nanjing, China.
• Bmc Med. 2025 Jan 23; 23 (1): 3838.

BackgroundIntermediate 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.MethodsWe 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.ResultsThe 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.ConclusionsThis 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.© 2025. The Author(s).

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