Bridging animal models and humans: neuroimaging as intermediate phenotypes linking genetic or stress factors to anhedonia

作者：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 · 发表于：BMC Medicine · 年份：2025 · DOI：10.1186/s12916-025-03850-4 · 被引用次数：7 · 研究领域：Neurotransmitter Receptor Influence on Behavior、Tryptophan and brain disorders、Stress Responses and Cortisol

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 o...