Our research largely consists of a three-pronged attack on the crucial problem of how the immune system modulates stress responses and susceptibility to depression. First, we are following up our discovery that the T cell subtype Th17 cells promote susceptibility to depression. Second, we identified critical signaling mechanisms by which stress induces an inflammatory response and identified a new potential therapeutic intervention ((+)-naloxone). Third, we identified the first specific signaling mechanism by which the gut microbiome releases a chemical signal (Autoinducer-2) to modulate depression sensitivity.
We discovered that a specific subtype of T cells called Th17 cells promote susceptibility to depressive-like behaviors in mice, and for which we identified feasible interventions. The overall objectives of this project are to identify characterize, localize and identify mechanisms of action of Th17 cells after stress and test the potential therapeutic impact of targeting Th17 cells to decrease vulnerability to depression, assessed by measuring depression-like behaviors in mice. This research evolved from the now well-established link between inflammation and depression. Inflammatory cytokines associated with depression drive the production of Th17 cells, and Th17 cells are already well-established to be toxic to the CNS. In mouse models, we found that Th17 cells are able to infiltrate mouse brain parenchyma after stress, these infiltrating cells exhibited characteristics of pathogenic (CCR6+ and IL-23R+) and follicular (CXCR5+) Th17 cells, and the presence of CCR6 on Th17 cells was required for them to promote depression-like behaviors in mice. However, the mechanisms of action of Th17 cells in depression remain to be identified.
Recent evidence has shown that alterations of the gut microbiota influence responses to stress. Microbiota also influences immune responses, in particular certain bacteria regulate the production of Th17 cells. Therefore, our overall hypotheses are that stress that induces depression-like behaviors in mice alters signals generated by certain residents of the microflora, that these signals promote the production of pathogenic Th17 cells, which in turn mediate the induction of depression-like behaviors after stress, and that establishment of depression augments changes in the microbiota that facilitates the continued susceptibility to depression, in part through up-regulated production of Th17 cells.
