PROJECT SUMMARY/ABSTRACT Depression is a leading cause of illness and disability worldwide, with a two-fold higher incidence in women than men. Stress is a well-established risk factor for depression. Studies to date showed that stress leads to epigenetic reprogramming of gene expression key for neuronal plasticity of brain circuits such as the ventral hippocampus, which has been implicated in depression. We previously reported that: 1) administration of acetyl-L-carnitine (LAC), leads to a rapid and persistent antidepressant-like response by increasing a chronic stress-induced suppression of H3K27ac and the related expression of a key inhibitor of glutamate release mGlu2 receptor in vDG glutamatergic neurons; and 2) LAC levels are decreased in subjects suffering from depression. The objective of this application is to understand the role of LAC-related mitochondrial metabolism in the regulation of stress responses. This contribution will advance our understanding of cellular and molecular mechanisms of mitochondrial metabolism for stress responses, and identify sex-differences in these mechanisms.