- Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.