Li Ming, Ren Kun, Cui Chi, Shi Yulong, Lei Jie, Li Tongxia, Yang Jian, Peng Xiang, Yang Xueke, Yao Yibo, Luo Gangan, Du Junsong, Chen Sitong, Zhang Pei, Tian Bo
Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China.
Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Neuropsychopharmacology. 2025 Jun 12. doi: 10.1038/s41386-025-02139-7.
Social animals encounter both environmental and social stress, yet the mechanisms by which individuals with different levels of trait anxiety cope with these stressors, as well as the neurobiological links between trait anxiety and social cognition, remain incompletely understood. Here, male mice are classified into high-trait anxiety (HTA) and low-trait anxiety (LTA) groups based on their anxiety responses to elevated platform exposure in the open field test. Under observational learning-based vicarious social defeat stress (VSDS), HTA mice exhibit less social avoidance behavior toward CD1 aggressors than LTA mice. Fiber photometry reveals that HTA mice display higher activity of ventral tegmental area (VTA) dopaminergic (VTA) neurons during environmental stress, while LTA mice exhibit greater VTA neurons activity under social stress. Viral tracing identifies the connectivity of VTA neurons and anterior cingulate cortex (ACC). Optogenetic and chemogenetic manipulations demonstrate that VTA-ACC dopaminergic circuit is necessary and sufficient for VSDS-induced social avoidance behavior in HTA and LTA mice. RNA-sequencing suggested that VTA neuroinflammatory signaling may be a key factor contributing to the difference between HTA and LTA mice. Thus, this study reveals a neural circuit mechanism for trait anxiety-related observational learning of social avoidance behavior in male mice, and provides a molecular mechanism in shaping trait anxiety.
群居动物会面临环境压力和社会压力，然而，具有不同特质焦虑水平的个体应对这些压力源的机制，以及特质焦虑与社会认知之间的神经生物学联系，仍未完全被理解。在此，基于雄性小鼠在旷场试验中对高架平台暴露的焦虑反应，将其分为高特质焦虑（HTA）组和低特质焦虑（LTA）组。在基于观察学习的替代性社会挫败应激（VSDS）下，HTA小鼠对CD1攻击者表现出的社会回避行为比LTA小鼠少。纤维光度法显示，在环境应激期间，HTA小鼠腹侧被盖区（VTA）多巴胺能神经元的活性较高，而LTA小鼠在社会应激下表现出更大的VTA神经元活性。病毒示踪确定了VTA神经元与前扣带回皮质（ACC）的连接性。光遗传学和化学遗传学操作表明，VTA-ACC多巴胺能回路对于HTA和LTA小鼠中VSDS诱导的社会回避行为是必要且充分的。RNA测序表明，VTA神经炎症信号可能是导致HTA和LTA小鼠差异的关键因素。因此，本研究揭示了雄性小鼠中与特质焦虑相关的社会回避行为观察学习的神经回路机制，并提供了塑造特质焦虑的分子机制。
