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

Anxiety is a psychiatric non-motor symptom of Parkinson's that can appear in the prodromal period, prior to significant loss of midbrain 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 (<i>Lrrk2</i> ^G2019S) and <i>Lrrk2</i> ^WT control mice. In humans, <i>LRRK2</i> ^G2019S significantly elevates the risk of late-onset Parkinson's. To assess within-sex differences between <i>Lrrk2</i> ^G2019S and control mice in stress-induced anxiety-like behaviors in young adulthood, we used a within-subject design whereby <i>Lrrk2</i> ^G2019S and <i>Lrrk2</i> ^WT control 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, male <i>Lrrk2</i> ^G2019S mice were affected similarly to male wildtypes except for novelty-suppressed feeding, where stress had no impact on <i>Lrrk2</i> ^G2019S mice while significantly increasing latency to feed in <i>Lrrk2</i> ^WT control mice. Female <i>Lrrk2</i> ^G2019S mice 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 female <i>Lrrk2</i> ^G2019S mice was generally lower compared to stressed <i>Lrrk2</i> ^WT mice, except for the nucleus accumbens of male <i>Lrrk2</i> ^G2019S mice, where cFos-labeled cell density was significantly higher than all other groups. Together, these data suggest that the <i>Lrrk2</i> ^G2019S mutation 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 some, but not all stress-related brain regions.