Stress-Free Voluntary Exercise Promotes Prophylactic Enhancement of Stress Resilience via the Nucleus Reuniens Affecting the Medial Prefrontal Cortex-Hippocampal Pathway.

Abstract

Stress is a risk factor for psychiatric illnesses. However, not all individuals exposed to stress will develop affective disorders. We examined whether pretreatment with stress-free voluntary wheel running (VWR) exercise prophylactically enhances stress resilience in rodents and how it can effectively prevent the development of depressive- and anxiety-like behaviors. Eight-week-old C57BL6/J mice were housed in cages with VWR and subjected to chronic restraint stress (CRST) for 2 h daily for 14 d. The mice were assessed for depressive- and anxiety-like behaviors, and a behavioral matrix (k-means clustering) was introduced to segregate the mice into susceptible and resilient subpopulations. Chemogenetic inhibition and retrograde tracing were used to map the neural circuits involved in VWR's resilience-enhancing properties. After CRST exposure, 71.50% of CRST mice with VWR were stress resilient, with less stress-induced prolonged activation of the hypothalamic-pituitary-adrenal axis and corticosterone (CORT) response, representing a 57.20% increase compared with CRST-only mice. Staining for c-Fos showed that VWR activated predominantly hippocampal GABAergic neurons and suppressed the activity in the medial prefrontal cortex (mPFC). Chemogenetic inhibition of the ventral hippocampus (vHPC) dissipated the antidepressant and anxiolytic effects of VWR pretreatment. In addition, the nucleus reuniens was implicated in VWR's resilience-enhancing properties, relaying reciprocal interactions of the mPFC-vHPC pathway. These findings suggest that stress-free voluntary exercise may be an effective modality for stress management and warrant further investigation into its resilience-enhancing mechanisms.