Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

项目总结 更好地了解能够抑制癫痫发作的网络，包括那些远离 癫痫的焦点，可能是开发癫痫所需新疗法的重要途径。 之前的工作，由K99/R00资助，发现小脑皮质的按需光遗传操作是 能够有力地抑制颞叶癫痫小鼠模型的海马区癫痫发作，具有最大的 通过调节中线小脑(蚯蚓)而产生的益处。 研究的关键领域来自之前的工作：1)观察到的功能连接性 延伸到健康的、非癫痫的动物身上？海马体中的哪些区域和细胞类型受到 小脑调节，以及哪些通路调节观察到的功能连接？2)如何 小脑干预导致癫痫发作抑制？具体地，需要什么形式的调制 小脑核团？最终通过什么途径成功地抑制癫痫发作？3)我们如何才能 这一信息(光遗传小脑调制可以更直接地抑制颞叶癫痫发作) 可翻译的？具体地说，小脑的电刺激能以这样一种方式进行吗 有力地抑制癫痫发作？哪些刺激参数是成功的关键？电刺激可以 当靶向小脑皮质时成功了吗？到原子核吗？是否定时(即按需) 干预重要吗？我们能通过小脑靶向干预来改善结果吗？回答这些问题 问题提高了先前研究结果的可译性，并为新的干预策略打开了大门。 我们发现，小脑对海马体的调制不仅限于癫痫抑制，而且 有些令人惊讶的是，初步数据显示，CA1地区受到了优惠影响， 包括抑制性中间神经元活性的增加。额外的初步数据表明， 顶核的光发生兴奋，而不是抑制，提供了癫痫控制。这使我们能够 进一步向下游探索，包括丘脑中央外侧核的顶端输入，追踪 功能连接通路。重要的是，我们还发现了电学而不是光学的干预 以小脑皮质为靶点能够抑制癫痫发作，但正如假设的那样，刺激参数 使用是成功的关键。可以通过以下方式成功识别适当的参数 贝叶斯参数优化，允许理性的、数据驱动的、闭环的参数方法 探险。综上所述，拟议中的实验不仅将提供对小脑的重要洞察- 海马区的相互作用，也借此抑制癫痫发作的网络能力，以及如何有效 使用临床上可用的电刺激工具瞄准这些网络。

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.