Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

PROJECT SUMMARY Decades ago, the cerebellum was explored as a potential target for the epilepsies. Mixed results ultimately reduced enthusiasm, but we have now shown that with the correct stimulation parameters, electrical stimulation of the cerebellar cortex can provide robust seizure control in a mouse model of temporal lobe epilepsy. During the previous funding period, we also demonstrated that optogenetic excitation of excitatory neurons in the cerebellar fastigial nucleus with projections to the central lateral thalamus (but not other populations of fastigial neurons) was able to inhibit hippocampal seizures. The fastigial nucleus may make a better target for deep brain stimulation than the cerebellar cortex. Unfortunately, it is not yet known if optimization of stimulation parameters can allow for robust seizure control when targeting the cerebellar nucleus (rather than cerebellar cortex) with on-demand electrical stimulation. In healthy animals, we further demonstrated that optogenetic stimulation of the cerebellum can cause a transient inhibition of CA1 pyramidal cells, and mixed, but structured, effects on CA1 interneurons. How cerebellar intervention in epilepsy impacts CA1 excitatory and inhibitory neuronal populations is unknown. Importantly, not only can the cerebellum impact seizures, but also seizures can impact the cerebellum, suggesting bidirectional functional modulation. In this proposal, we therefore examine 1) the impact of on-demand cerebellar stimulation on CA1 principle and inhibitory interneuron populations in chronically epileptic animals, 2) the impact of seizures on cerebellar fastigial and central lateral thalamic neurons, and the impact of on-demand optogenetic intervention targeting the fastigial nucleus on the central lateral nucleus, and 3) if, with Bayesian optimization, electrical stimulation of the fastigial nucleus can be an effective strategy, if this outperforms targeting of a different cerebellar nucleus (the dentate nucleus), and if targeting the downstream central lateral nucleus can also be an effective approach. Collectively, this data will significantly improve our understanding of temporal lobe seizure networks (extending far beyond the temporal lobe), improve our understanding of how cerebellar modulation may result in seizure inhibition, and ultimately identify potential new intervention strategies.