Mechanisms of age- and sex-specific stress and immune reactivity.

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The overarching objective of this proposal is to identify the potential mechanisms through which the gonadal steroid hormones and the gut-brain axis interact and induce age and sex differences in normative stress and immune reactivity. The stress and immune systems are intimately related and communicate in a bidirectional manner. Lipopolysaccharide (LPS) is a common laboratory stressor used to elicit both stress and immune responses. My laboratory and others have shown that LPS exposure elicits age and sex-specific stress and immune responses. The existing literature suggests that pubertal gonadal steroid hormones initiate the maturation of the HPA axis and of the immune system and facilitate the development and expression of sex differences in stress and immune reactivity. However, the mechanisms through which gonadal steroid hormones influence the development of the HPA axis during puberty remain elusive. The gut microbiome also regulates stress and immune responses through the gut-brain axis, but the underlying mechanisms are still unclear. Therefore, specific objective 1 will identify the role of gonadal sex hormones and the underlying genetic and epigenetic mechanisms of gonadal function in the modulation of age- and sex-related differences in acute peripheral and central stress and immune responses in mice. Then, in specific objective 2, we will investigate the role of gonadal sex hormones in the modulation of age- and sex-related differences in blood-brain barrier permeability and microglial function in the brain. Finally, specific objective 3 will examine the role of the gut-brain axis in the age- and sex-specific stress and immune responses. The proposed objectives build on my previous NSERC funded research program and use an innovative and transformative line of inquiry in the NSE to significantly advance our understanding of the endocrine and microbial factors that induce normative age and sex differences in stress and immune reactivity. The results generated by the proposed research program will be suitable for dissemination to the public, stakeholders and research community. This research program will also provide my trainees with a variety of transferable technical, practical and soft skills that will help them regardless of their career orientation.