Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress

Abstract

Anxiety is a psychiatric non-motor symptom of Parkinson’s that can appear in the prodromal period, prior to significant loss of brainstem dopamine neurons and motor symptoms. Parkinson’s-related anxiety affects females more than males, despite the greater prevalence of Parkinson’s in males. How stress, anxiety and Parkinson’s are related and the basis for a sex-specific impact of stress in Parkinson’s are not clear. We addressed this using young adult male and female mice carrying a G2019S knockin mutation of leucine-rich repeat kinase 2 (Lrrk2G2019S) andLrrk2WTcontrol mice. In humans,LRRK2G2019Ssignificantly elevates the risk of late-onset Parkinson’s. To assess within-sex differences betweenLrrk2G2019Sand control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design wherebyLrrk2G2019SandLrrk2WTcontrol mice underwent tests of anxiety-like behaviors before (baseline) and following a 28 day (d) variable stress paradigm. There were no differences in behavioral measures between genotypes in males or females at baseline, indicating that the mutation alone does not produce anxiety-like responses. Following chronic stress, maleLrrk2G2019Smice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact onLrrk2G2019Smice while significantly increasing latency to feed inLrrk2WTcontrol mice. FemaleLrrk2G2019Smice were impacted by chronic stress similarly to wildtype females across all behavioral measures. Subsequent post-stress analyses compared cFos immunolabeling-based cellular activity patterns across several stress-relevant brain regions. The density of cFos-activated neurons across brain regions in both male and femaleLrrk2G2019Smice was generally lower compared to stressedLrrk2WTmice, except for the nucleus accumbens of maleLrrk2G2019Smice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that theLrrk2G2019Smutation differentially impacts anxiety-like behavioral responses to chronic stress in males and females that may reflect sex-specific adaptations observed in circuit activation patterns in stress-related brain regions.