Mapping the Cerebello-Hippocampal Circuit: Normative Patterns and Sex-Dependent Connectivity

Abstract

Cerebello-hippocampal (CB-HP) interactions have been implicated in spatial abilities and reinforcement learning, yet their relationship to behavior and differences in connectivity with sex in early adulthood are unclear. Resting CB-HP network patterns have yet to be established in young adults. Mapping the normative resting-state CB-HP connectivity pattern is essential for identifying when CB-HP circuitry becomes behaviorally relevant across the lifespan and for detecting early circuit-level deviations that may precede neurodegenerative or endocrine disruption. We combined resting-state functional MRI (rsfMRI) with measures of cognition in 1,081 healthy young adults (22-37 years, 54% women) from the Human Connectome Project S1200 to map CB-HP functional connectivity (FC), examine sex differences, and define its relationship with performance across episodic memory, visuospatial, and executive function tasks. Region of interest (ROI)-to-ROI FC between the right cerebellum and left hippocampus were quantified. In our CB-HP mapping, we found: 1) negative relationships between the entire HP axis and cerebellar regions: vermis VII; lobules VI, VIIb, and VIII; Crus I & II, and 2) positive relationships between most of the HP axis and ventral/medial cerebellar regions. We revealed sex differences in CB-HP such that females had greater FC than males between anterior to mid-hippocampal regions and medial cerebellar regions: vermis IV-VI; lobules VI, VIII, IX; and Crus II. We predicted CB-HP FC patterns would show strong positive associations with cognitive measures (i.e., episodic memory, visuospatial processing, working memory, and executive function); however, we did not find any associations after multiple comparisons correction (pFDR > 0.05). Together, our findings detail a functional atlas of the CB-HP circuit in young adulthood and highlight sex differences within. Our results provide a foundation for understanding functionally-based gradients between these two regions.