Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

项目概要 更好地了解能够抑制癫痫发作的网络，包括那些远离癫痫发作的网络 癫痫焦点可能是开发所需的癫痫新疗法的重要途径。 先前由 K99/R00 资助的工作发现，对小脑皮层的按需光遗传学操作是 能够强有力地抑制颞叶癫痫小鼠模型的海马癫痫发作， 通过调节小脑中线（蚓部）产生的益处。 研究的关键领域源于这项先前的工作：1）观察到的功能连接是否存在？ 扩展到健康、非癫痫动物？海马体中的哪些区域和细胞类型受到影响 小脑调节，以及哪些途径介导观察到的功能连接？ 2）如何 小脑定向干预会抑制癫痫发作吗？具体来说，需要什么形式的调制 小脑核？什么途径最终介导成功抑制癫痫发作？ 3）我们怎样才能使 这个信息（光遗传学小脑调节可以抑制颞叶癫痫发作）更直接 可翻译吗？具体来说，对小脑的电刺激是否可以以这样的方式进行： 强烈抑制癫痫发作？哪些刺激参数对于成功至关重要？电刺激可以吗 针对小脑皮层是否成功？到原子核？是否定时（即按需） 干预有什么关系？我们可以通过小脑针对性干预来改善结果吗？回答这些 问题提高了先前发现的可转化性，并为新的干预策略打开了大门。 我们发现海马体的小脑调节不仅限于抑制癫痫发作，而且 有点令人惊讶的是，初步数据表明 CA1 区域受到优先影响， 包括抑制性中间神经元活性的增加。额外的初步数据表明 顶核的光遗传学激发而非抑制提供了癫痫发作控制。这使我们能够 进一步探索下游，包括丘脑中央外侧核的顶输入，追踪 功能连接通路。重要的是，我们还发现电气干预，而不是光学干预 针对小脑皮层能够抑制癫痫发作，但是，正如假设的那样，刺激参数 使用对于成功至关重要。可以通过以下方式成功识别适当的参数 贝叶斯参数优化，允许采用合理的、数据驱动的、闭环的参数方法 探索。总而言之，所提出的实验不仅将为小脑提供重要的见解 海马相互作用，以及能够抑制癫痫发作的网络，以及如何有效地 使用临床上可用的电刺激工具来瞄准这些网络。

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.