Peking 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), Beijing, 100191, China.
Neuropsychopharmacology. 2024 Oct;49(11):1666-1677. doi: 10.1038/s41386-024-01848-9. Epub 2024 Mar 19.
Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.
目睹暴力或创伤性事件在儿童和青少年时期很常见，可能会导致有害影响，如增加患精神障碍的风险。这种应激源可以在青少年实验室动物中使用慢性目击社交挫败（CWSD）范式来模拟，但 CWSD 在青少年动物中的行为后果仍有待验证，包括认知、焦虑样和抑郁样行为，更重要的是，潜在的神经机制仍有待揭示。在这项研究中，我们首先在青春期雄性小鼠中建立了 CWSD 模型，发现 CWSD 损害了认知功能，增加了焦虑水平，并且这些行为缺陷持续到成年期。基于海马体的背-腹功能分区，我们在行为任务后进行了即时早期基因 c-fos 免疫染色，发现 CWSD 引起的认知缺陷与背侧 CA3 过度兴奋有关，而焦虑样行为与腹侧 CA3 活动减少有关。事实上，背侧 CA3 神经元的化学遗传激活和抑制分别模拟和逆转了 CWSD 诱导的识别记忆缺陷（而非焦虑样行为），而腹侧 CA3 神经元的抑制和激活均增加了青春期小鼠的焦虑样行为。最后，慢性给予文拉法辛（一种新型多模态抗抑郁药）成功恢复了 CWSD 小鼠背侧 CA3 神经元的过度兴奋和认知缺陷。总之，我们的研究结果表明，背侧 CA3 过度兴奋介导了 CWSD 诱导的青春期雄性小鼠识别记忆缺陷，为青少年 CWSD 诱导的不良影响的病理生理学提供了线索，并为应激诱导的认知缺陷的早期治疗提供了临床前证据。
