PROJECT SUMMARY A greater understanding of the networks capable of suppressing seizures, including those remote from the seizure focus, may be an important avenue towards developing needed new therapies for the epilepsies. Prior work, funded by a K99/R00, found that on-demand optogenetic manipulation of the cerebellar cortex was able to robustly inhibit hippocampal seizures in a mouse model of temporal lobe epilepsy, with the greatest benefits occurring through modulation of the midline cerebellum (vermis). Key areas of investigation arise from this prior work: 1) Does this observed functional connectivity extend to healthy, non-epileptic animals? What regions and cell-types in the hippocampus are impacted by cerebellar modulation, and what pathways mediates the observed functional connectivity? 2) How does cerebellar-directed intervention lead to seizure inhibition? Specifically, what form of modulation is required of the cerebellar nuclei? What pathways ultimately mediates successful seizure inhibition? 3) How can we make this information (that optogenetic cerebellar modulation can inhibit temporal lobe seizures) more directly translatable? Specifically, can electrical stimulation of the cerebellum be done in such a way as to also robustly inhibit seizures? What stimulation parameters are critical for success? Can electrical stimulation be successful when targeted to the cerebellar cortex? To the nuclei? Does the timing (i.e. on-demand) of intervention matter? Can we improve outcomes through cerebellar targeted interventions? Answering these questions improve translatability of previous findings and opens the door to novel intervention strategies. We find that cerebellar modulation of the hippocampus is not limited to seizure suppression, and somewhat surprisingly, preliminary data indicates that there is a preferential impact on the CA1 region, including an increase in activity of inhibitory interneurons. Additional preliminary data suggests that optogenetic excitation, but not inhibition, of the fastigial nucleus provides seizure control. This allows us to explore further downstream, including fastigial inputs to the central lateral nucleus of the thalamus, tracing the functional connectivity pathway. Importantly, we are also finding that electrical, rather than optical, intervention targeting the cerebellar cortex is able to inhibit seizures, but, as hypothesized, that the stimulation parameters used are critical for success. Successful identification of appropriate parameters is achievable through Bayesian Parameter Optimization, which allows a rational, data driven, closed-loop approach to parameter exploration. Taken together, the proposed experiments will provide important insight not only into cerebellar- hippocampal interactions, but also thereby networks capable of seizure suppression, and how to effectively target those networks using the clinically available tool of electrical stimulation.