Hippobellum: Cerebellar influence on the hippocampus and temporal lobe seizures

Hippobellum：小脑对海马体和颞叶癫痫发作的影响

• 批准号: 10529310
• 负责人: Esther Krook-Magnuson
• 金额: $ 43.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529310
• 关键词: Adult; Affect; Animals; Anterior; Area; Brain region; Cell Nucleus; Central Lateral Nucleus; Cerebellar Cortex; Cerebellar Nuclei; Cerebellar vermis structure; Cerebellum; Chronic; Clinical; Data; Electric Stimulation; Electrophysiology (science); Epilepsy; Fiber; Funding; Future; Hippocampus; Immunohistochemistry; Interneurons; Intervention; Investigation; Lead; Literature; Mediating; Methods; Neurons; Nucleus fastigii; Optics; Outcome; Output; Pathway interactions; Patients; Seizures; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Thalamic structure; Time; Work; behavioral outcome; cell type; cingulate cortex; design; experimental study; improved; improved outcome; in vivo; in vivo calcium imaging; insight; mouse model; new therapeutic target; novel; novel therapeutics; optogenetics; public health relevance; success; successful intervention; tool; translational potential

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.

项目摘要 更好地了解能够抑制缉获的网络，包括那些远离 癫痫发作的重点，可能是一个重要的途径，朝着发展所需的新疗法的癫痫。 之前的工作，由K99/R 00资助，发现小脑皮层的按需光遗传学操作是 能够在颞叶癫痫小鼠模型中强烈抑制海马癫痫发作， 通过调节中线小脑（蚓部）而产生的益处。 研究的关键领域来自于先前的工作：1）观察到的功能连接性 扩展到健康的非癫痫动物身上海马体中的哪些区域和细胞类型受到 小脑调制，以及什么途径介导观察到的功能连接？2)如何 小脑定向干预导致癫痫发作抑制？具体来说，需要什么形式的调制， 小脑核团什么途径最终介导成功的癫痫抑制？3)我们怎样才能使 这一信息（光遗传小脑调节可以抑制颞叶癫痫发作）更直接 可翻译的？具体来说，小脑的电刺激是否可以以这样一种方式进行， 抑制癫痫发作哪些刺激参数对成功至关重要？电刺激可以 成功地瞄准了小脑皮质去原子核？是否定时（即按需） 干预的重要性？我们能通过小脑靶向干预改善预后吗？回答这些 问题提高了先前发现的可翻译性，并为新的干预策略打开了大门。 我们发现小脑对海马的调节不仅限于抑制癫痫发作， 有些令人惊讶的是，初步数据表明，对CA 1区域有优先影响， 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 功能性连接途径。重要的是，我们还发现，电子，而不是光学，干预， 靶向小脑皮质能够抑制癫痫发作，但是，正如假设的那样，刺激参数 使用是成功的关键。通过以下方法可以成功识别适当的参数： Bayesian参数优化，它允许一个合理的，数据驱动的，闭环的方法来参数 探索总之，拟议的实验将提供重要的见解，不仅小脑- 海马体的相互作用，而且因此网络能够抑制癫痫发作，以及如何有效地 使用临床上可用的电刺激工具瞄准这些网络。