Project Summary Chronic psychosocial stress is a major risk factor for functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Notably, there is high co-morbidity between IBS and stress-related psychiatric disorders such as major depressive disorder (MDD), with IBS and MDD representing two of the most prevalent and debilitating illnesses worldwide. Potentially underlying this co-morbidity is the recent finding that chronic stress elicits low-grade inflammation, which has been associated with both IBS and MDD. Moreover, increasing evidence suggests that the gut-brain axis, or connections between the central and enteric nervous systems, contributes to the etiology of IBS. However, the mechanisms through which an emotional state such as chronic stress influences gut pathophysiology, including inflammation, remain poorly understood. In preliminary experiments using the chronic social defeat stress (CSDS) model in mice, we find that intestinal inflammation and barrier permeability become elevated following CSDS in both male and female mice, and these phenomena correlate with depression-like behaviors such as social avoidance. In this project, I will investigate how psychosocial stress causes this gut pathophysiology. Using retrograde viral tracing strategies from the gut to the brain, and whole-brain imaging, I have generated a list of candidate stress-activated brain regions that directly innervate the gut. In the first aim of this proposal, I will use integrated neuroscience and immunology techniques, such as chemogenetics and flow cytometry, to determine if activation of these brain regions can trigger gut inflammation and barrier permeability. Moreover, I aim to identify subsets of enteric neurons in the intestine that receive signals from the brain during stress to propagate IBS-like symptoms. In the second aim, I will then assess how inflammatory signals in the gut are conveyed to the brain to influence stress-relevant behaviors. As the brain can detect the inflammatory state of peripheral tissues through sensory afferent nerves, I will first identify which stress-responsive brain regions receive input from gut. I will then use fiber photometry to evaluate how gut inflammation modulates neuronal activity in these brain regions and its consequences on behavior. In parallel, I will investigate if a compromised intestinal barrier allows bacterial toxin translocation from the gut lumen into circulation to promote systemic inflammation and depression-like behaviors. Collectively, this project aims to define bi-directional stress-activated gut-brain circuits that contribute to IBS- and MDD-related symptoms.