Grant: Discovery Grants Program - Individual

Individuals experiencing socially stressful situations on a regular basis may suffer from cognitive deficits. Using mouse models, we showed that beyond their effects on stress hormones or neurotransmitters, social stressors increased pro-inflammatory cytokines (immune signaling molecules) in the bloodstream and in brain regions associated with cognition (e.g., hippocampus and prefrontal cortex). This is important as on a chronic basis, brain inflammatory activation may damage other systems, including those implicated in cognition, suggesting that collateral damages linked to long-lasting neuroinflammation could promote cognitive impairments. Importantly, how stressors elicit brain cytokine elevations and how these come to affect cognition are not fully understood. Microbes that inhabit the digestive tract, referred to as the gut microbiota, were implicated in the development and maintenance of the innate and adaptive immune systems. Although the mechanisms underlying the communication between gut microbes and the host brain have yet to be entirely uncovered, routes involving the signaling of key inflammatory molecules have been positioned as crucial channels by which these two systems talk to each other. Using social defeat, a stressor particularly effective in increasing pro-inflammatory cytokines in the bloodstream and the brain in mouse models, we showed that some bacteria increased by the stressor were linked to the expression of pro-inflammatory cytokines in the brain. We also showed that inflammatory changes in the gut microbiota and alterations in intestinal tight junctions after chronic stress differed among female and male mice. These findings suggest that stress-induced pro-inflammatory shifts within the intestinal milieu, combined with an opening of the intestinal barrier, could promote extra-intestinal inflammatory activation differently in females and males, potentially ramifying to the brain in a sex-dependent way. How gut bacteria elicit these sex-specific outcomes when "stressed", with impact on cognition, remains to be determined. My research program will examine the mechanisms by which gut bacteria promote a pro-inflammatory crosstalk between the gut and brain upon social stress, leading to altered cognition. After establishing the temporal sequence of social stressor effects on the gut microbiota-immune-brain axis and cognition, we will use different approaches to modulate the gut microbiota (e.g., antibiotics) or inflammatory processes (e.g., agents blocking inflammatory signaling pathways) on stress-induced outcomes. Based on findings in my lab showing that microbiota changes upon social stressor exposure and lifestyle interventions are sex-specific, we will conduct these experiments in both females and males. These innovative studies will be crucial in our understanding of the sex differences that may define the reciprocal interactions between the gut microbiota and the host brain under stress, with impact on cognition.