Elucidating mechanisms by which physical exercise promotes resilience, the brain's ability to cope with prolonged stress exposure while maintaining normal psychological functioning, is a major research challenge given the high prevalence of stress-related mental disorders, including major depressive disorder. Chronic voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise, induces the transcription factor ΔFosB in the nucleus accumbens (NAc), a key reward-related brain area. ΔFosB expression in NAc modulates stress susceptibility. Here, we explored whether VWR induction of NAc ΔFosB promotes resilience to chronic social defeat stress (CSDS). Male young-adult C57BL/6J mice were single housed for up to 21 d with or without running wheels and then subjected to 10 d of CSDS. Stress-exposed sedentary mice developed a depressive-like state, characterized by anhedonia and social avoidance, whereas stress-exposed mice that had been wheel running showed resilience. Functional inhibition of NAc ΔFosB during VWR, by viral-mediated overexpression of a transcriptionally inactive JunD mutant, reinstated susceptibility to CSDS. Within the NAc, VWR induction of ΔFosB was CREB-dependent, associated with altered dendritic morphology, and medium spiny neuron (MSN) subtype specific in the NAc core and shell subregions. Finally, when mice performed VWR following the onset of CSDS-induced social avoidance, VWR normalized such behavior. These data indicate that VWR promoted resilience to CSDS, and suggest that sustained induction of ΔFosB in the NAc underlies, at least in part, the stress resilience mediated by VWR. These findings provide a potential framework for the development of treatments for stress-associated mental illnesses based on physical exercise.

中文翻译：

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自愿跑轮可提高小鼠对慢性社交挫败压力的恢复能力：伏隔核 ΔFosB 的作用。


鉴于与压力相关的精神障碍（包括重度抑郁症）的高患病率，阐明体育锻炼促进恢复力（大脑应对长期压力暴露同时保持正常心理功能的能力）的机制是一项重大研究挑战。慢性自愿轮跑（VWR）是一种模仿人类体育锻炼的啮齿动物模型，可在伏隔核（NAc）（与奖励相关的关键大脑区域）中诱导转录因子 ΔFosB。 NAc 中的 ΔFosB 表达调节应激敏感性。在这里，我们探讨了 NAc ΔFosB 的 VWR 诱导是否可以促进慢性社交失败压力 (CSDS) 的恢复能力。将雄性年轻成年 C57BL/6J 小鼠单独圈养长达 21 天，带或不带跑轮，然后进行 10 天的 CSDS。受到压力的久坐小鼠会出现类似抑郁的状态，其特征是快感缺失和社交回避，而受到压力的、一直在轮子上奔跑的小鼠则表现出恢复能力。通过病毒介导的转录失活 JunD 突变体的过表达，在 VWR 期间对 NAc ΔFosB 进行功能性抑制，从而恢复对 CSDS 的敏感性。在 NAc 内，ΔFosB 的 VWR 诱导是 CREB ​​依赖性的，与树突形态的改变以及 NAc 核心和壳亚区特异的中型多棘神经元 (MSN) 亚型相关。最后，当小鼠在 CSDS 诱导的社交回避开始后进行 VWR 时，VWR 使这种行为正常化。这些数据表明，VWR 促进了 CSDS 的恢复力，并表明 NAc 中 ΔFosB 的持续诱导至少部分是 VWR 介导的应激恢复力的基础。 这些发现为开发基于体育锻炼的压力相关精神疾病的治疗方法提供了潜在的框架。