A Study of the Gut-Brain Axis in Stress-Induced Depression

Part 1: Current treatments for major depressive disorder are limited to neuropharmacological approaches and are ineffective for large numbers of patients. Recently, alternative means have been explored to understand the etiology of depression. Specifically, changes in the immune system have been observed in both clinical settings and in mouse models. As inflammatory RORgt+ CD4+ Th17 T cells and their primary cytokine IL-17 have been implicated in the development of stress-induced depression, the connection between stress, Th17s, and depression remains critical to disease understanding. Here, we utilized a CD4-specific RAR Related Orphan Receptor C (Rorc) knockout line to disrupt the production of Th17s. Mice lacking Rorc produced IL-17 did not show any differences in behavior before or after stress when compared to controls. Additionally, we utilize an unsupervised machine learning system to examine minute differences in behavior that could not be observed by traditional behavioral assays. Our data demonstrate that CD4 specific Rorc is not necessary for the development of stress-induced anxiety- or depressive-like behaviors. These data suggest that research approaches should focus on other sources or sites of IL-17 production in stress-induced depression.

Part 2: Depression is a common mental health condition with a large impact on the economy and society. While depression etiology is multifactorial; chronic stress is a well-accepted contributor to the disease. Depression is associated with altered gut microbial signatures that can be replicated in animal models. While targeted restoration of the microbiome has been shown to reduce depressive-like behaviors in mice, the complexity and diversity of the human microbiome has complicated therapeutic intervention in patients. To circumvent the current microbiome therapeutic limitations, there is a critical need for identifying pathways responsible for microbiome dysbiosis. Here, we identify that that the mucosal layer, and specifically, expression of the transmembrane protein mucin 13, can regulate microbiome composition in a model of stress-induced depression. To demonstrate this, we use a model of unpredictable chronic mild stress to induce anxiety- and depressive-like behaviors in mice and alter the microbiome. After stress exposure, we a significant reduction in mucin 13 expression across the intestines. We further present gene expression data correlating Muc13 expression reductions and stress- induced alterations in circadian rhythms. Furthermore, we show that deleting Muc13 leads to gut dysbiosis, and baseline behavioral changes normally observed after stress exposure. Lastly, we demonstrate that Muc13 deletion increases susceptibility to stress-induced behavioral changes. Together, these results demonstrate that mucosal layer disruption is an initiating event in stress- induced dysbiosis and offers mucin 13 as a potential new therapeutic target for microbiome dysbiosis in stress-induced depression.