Proposal of a novel mechanism of depression caused by chronic stress: Disruption of energy metabolism in the brain

Abstract

Although depression has a very high lifetime incidence rate of 10%, the remission rate of existing antidepressants is low, and the discovery of new drug targets is urgently needed. On the other hand, large-scale genome-wide association study analysis revealed Sirt1 as a genomic region associated with depression, and because Sirt1 is a factor involved in the regulation of mitochondrial activity, we focused on mitochondria in the present study to examine their relevance to depression. Mice showed depressed- and anxiety-like behaviors when subjected to chronic restraint stress. These mouse brain mitochondrial specimens had significantly reduced oxygen consumption rates and expression of electron transfer chain proteins. Furthermore, mitochondria-specific unfolded protein stress responses (UPRmt) was significantly correlated with the depression-like behavior of mice. Antibiotics that inhibit protein synthesis have been reported to induce UPRmt. We found that doxycycline had antidepressant- and anxiolytic-like effects in mice when it was chronically applied to them. These results indicate that UPRmt may be involved in depressive- and anxiety-like behaviors in mice.