PROJECT SUMMARY/ABSTRACT Treatment resistant depression (TRD) is a leading cause of illness and disability worldwide; there is a dearth of new mechanistic models for the development of better therapeutic strategies. Studies to date showed that administration of LAC, a pivotal mitochondrial metabolite, leads to a rapid and persistent antidepressant-like response by increasing histone acetyltransferases (HATs) activity and the related expression of a key inhibitor of glutamate release mGlu2 receptor in circuits implicated in TRD. Furthermore, LAC levels are decreased in clinical phenotypes of TRD. The objective of this application is to understand the role of central and peripheral LAC-related mitochondrial metabolism in the regulation of TMS responses in phenotypes of TRD. We will also use computational algorithm and statistical clustering to ascertain the role of the novel biomarkers of TMS responses in the trajectories of functional connectivity, and how these pathways are modified by sex. This contribution will advance our understanding of cellular and molecular mechanisms of mitochondrial metabolism for TMS responses in phenotypes of TRD, and identify sex-differences in these mechanisms.

PROJECT NARRATIVE The proposed research is relevant to the public because treatment resistant depression (TRD) is increasing in prevalence and represents a significant national cost. Motivated by our recent findings of decreased levels of acetyl-L- carnitine (LAC) in TRD, we seek to understand the role of central and peripheral mitochondrial metabolism of LAC in the effects of TMS-related effects on resting state functional connectivity and clinical responses. This work will lead to development of new multidimensional models of brain-body metabolic crosstalk and development of new therapeutic strategies.