Exercise Leverages a Post-Stress Therapeutic Window in Hypothalamic CRH Neurons to Enable Recovery from Threat Sensitization

Exercise provides a range of benefits for physical and mental health. It relieves stress, yet paradoxically, it recruits the bodys stress response system. Here we show that activation of corticotropin-releasing hormone cells of the paraventricular nucleus of the hypothalamus (CRHPVN) and the endocrine arm of the stress axis is necessary, but not sufficient for the beneficial effects of exercise. Specifically, glucocorticoids act synergistically with brain-derived neurotrophic factor (BDNF) on CRHPVN cells during exercise to reverse behavioral and synaptic sensitization after stress. In the absence of exercise, optogenetic activation of the tropomyosin-related kinase B (TrkB) receptor after stress is sufficient to reverse behavioral sensitization and synaptic metaplasticity. Our findings reveal a novel, time-sensitive mechanism by which exercise alleviates the impact of acute stress.