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

Abstract Exercise provides a range of benefits for physical and mental health. It relieves stress, yet paradoxically, it recruits the body’s stress response system. Here we show that activation of corticotropin-releasing hormone cells of the paraventricular nucleus of the hypothalamus (CRH PVN ) 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 CRH PVN 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.