The Role of the Cerebello-Hippocampal Circuit: Exploring its Relationship to Sex Differences and Cognition in Aging

Abstract Objective Healthy aging is linked to declines in cognition and motor functioning which have an impact on quality of life and independence. Females are at greater risk for cognitive decline secondary to Alzheimer’s disease (AD) which may be due to significant sex steroid hormone declines with menopause. Diminished estradiol has been linked to greater AD risk and pathogenesis in aging. Notably, the hippocampus and cerebellum are dense with estrogen and progesterone receptors. Here, we investigate a novel neural circuit (cerebello-hippocampal; CB-HP) in the context of behavior, sex differences, and hormone levels in healthy aging to advance understanding of cognitive decline in the aging population. Method 138 healthy adults (aged 35–86, 53% female) completed resting-state functional connectivity (FC) MRI. We analyzed region of interest (ROI)-to-ROI correlations with behavioral assessments (i.e., WAIS-IV Letter-Number Sequencing, WMS-IV Symbol Span, Stroop, Shopping List Memory, Sequence Learning, Purdue Pegboard Assembly) and sex hormone (estradiol and progesterone) levels. Linear regressions evaluated relationships between sex hormone levels and behavioral performance. Results We found greater CB-HP FC with higher levels of estradiol (see figure). We also found lower CB-HP FC with increased age and higher levels of progesterone. There were no significant associations between behavioral tasks and connectivity or hormones. Conclusion These results were consistent with literature on FC and sex hormones in aging. Our results did not indicate associations between CB-HP FC and behavior in healthy aging adults. Our findings underscore the CB-HP circuit’s role in aging in the context of sex hormone levels.