The role of the nucleus accumbens in exercise-induced stress resistance

About This Grant

PROJECT SUMMARY The prevalence of stress-related disorders has surged globally. Although females are twice as likely as males to develop a stress-related disorder, they remain markedly underrepresented in preclinical research investigating stress resistance factors and their associated mechanistic pathways. Exercise is an important resistance factor with a broad range of stress-buffering effects that are not only highly conserved across species but develop more rapidly in females than males. Preclinical models demonstrate that voluntary wheel running (VWR) prevents the typical depressive- and anxiety-like outcomes of inescapable stress (IS) in rats, and importantly, females attain stress resistance more rapidly (3 weeks of VWR) than males (6 weeks of VWR). Exercise affords behavioral stress resistance at these timepoints by constraining the serotonergic (5HT) response in the dorsal raphe nucleus (DRN), however the mechanisms underlying this constraint are unknown. My preliminary data reveal a robust inhibitory pathway from the nucleus accumbens (NAc) to the DRN that is positioned to inhibit the activity of DRN 5HT neurons during stress and is primed by prior exercise. This proposal explores whether the NAc is critical for the protective stress effects of exercise, at least in part, through GABAergic projections to DRN 5HT neurons. My preliminary data reveal that 6 weeks of VWR in males potentiates IS-induced activity of DRN-projecting NAc neurons. Notably, the NAc displays differences in neural morphology and enhanced stimulus-evoked dopamine females, which could account for the accelerated acquisition of exercise-induced stress resistance in female rats. Aim 1 will examine whether prior VWR engages the NAc-DRN pathway during IS in both sexes, and whether this process occurs earlier in females compared to males, using viral tracing and fluorescent in situ hybridization. Given the temporal differences of stress resistance between VWR males and females, I hypothesize that prior exercise will increase IS-induced cfos in DRN-projecting GABAergic NAc neurons in males after 6 weeks and in females (but not males) after 3 weeks. Aim 2A will examine whether chemogenetic inhibition of the NAc-DRN pathway during IS will prevent exercise-induced resistance to the behavioral outcomes of IS, such as social avoidance and exaggerated fear. Aim 2B will utilize in vivo fiber photometry to examine whether chemogenetic inhibition of the NAc-DRN pathway during IS restores the DRN 5HT response to IS, despite sufficient exercise experience. Preliminary data suggest that males recruit multiple mechanisms for the stress-protective effects of exercise, such as IS- induced activity from prefrontal cortical neurons. In contrast, my preliminary data suggest that females rely on the NAc-DRN pathway as a single, distinct stress resistance mechanism. Therefore, I hypothesize that NAc- DRN pathway inhibition during IS will eliminate the protective effects of VWR on IS-induced 2A) behavioral outcomes and 2B) DRN 5HT activity in female, but not male rats. Collectively, this proposal aims to investigate the underlying mechanisms of exercise-induced stress resistance and the sex differences therein.