Connectivity of the right cerebello-left hippocampal circuit across adulthood

Direct communication between the hippocampus and cerebellum has been shown via coactivation and synchronized neuronal oscillations in animal models. Further, the cerebello-hippocampal circuit has been under-investigated in the human brain and may be impacted by sex steroid hormones. The cerebellum and hippocampus are dense with estradiol and progesterone receptors relative to other brain regions. Females experience up to a 90% decrease in ovarian estradiol production after the menopausal transition. Postmenopausal women show lower cerebello-cortical functional connectivity (FC) compared to reproductive aged females. Further, sex hormones are established modulators of both memory function and synaptic organization in the hippocampus in non-human animal studies. However, investigation of the cerebello-hippocampal (CB-HP) circuit has been limited to animal studies and small homogeneous samples of young adults as it relates to spatial navigation. Here, we investigate the CB(right)-HP(left) circuit in 138 adult humans (53% female) from 35-86 years of age, to define its FC patterns, and investigate its associations with behavior, hormone levels, and sex differences therein. We demonstrated robust FC patterns between the right CB and left HP in this sample. We predicted and found negative relationships between age and CB-HP FC. As expected, estradiol levels exhibited positive relationships with CB-HP connectivity. We found lower CB-HP FC with higher levels of progesterone. We provide the first characterization of the CB-HP circuit across middle and older adulthood and demonstrate that connectivity is sensitive to sex steroid hormone levels. This work provides the first clear CB-HP circuit functional mapping in the human brain and serves as a foundation for future work in neurological and psychiatric diseases.