On-demand optogenetic cerebellar intervention for temporal lobe epilepsy

描述（由申请人提供）：癫痫是一种反复发作的疾病。仅在美国，每天就有近500例新的癫痫病例被诊断出来，每年有多达5万例与癫痫相关的死亡。颞叶癫痫是成人中最常见的癫痫形式，与认知能力下降有关。对于40%以上的患者，目前的治疗方案无法控制癫痫发作，全身性抗癫痫药物可能产生严重的负面副作用。需要新的治疗方案。在颞叶癫痫小鼠模型中，按需光遗传学，通过实时的癫痫检测触发将光传递到海马体（颞叶癫痫的关键大脑结构），可以阻止自发癫痫发作。这些技术还提供了一个独特的机会来调查与癫痫发作有关的关键网络。本研究利用随需随用光遗传学、体内近细胞记录和颞叶癫痫小鼠海马内盐盐模型的行为测试，研究了癫痫发作和海马依赖性认知过程中小脑-海马相互作用的作用。通过认识到小脑抑制癫痫发作的能力，并确定其介导的机制，我们不仅对癫痫发作有了深入的了解，而且还为治疗这种普遍而严重的疾病找到了新的治疗靶点和策略。我对网络和神经元多样性及其在生理过程和疾病中的作用感兴趣。我的职业目标包括成为一名独立研究员，研究癫痫和疾病，这可能会为癫痫提供更多的见解。癫痫研究中仍存在一些关键问题，包括启动、维持、传播、终止和潜在抑制颞叶癫痫发作的关键网络和条件是什么。通过提高我们对这些的理解，我们提高了有一天实现所有癫痫患者无癫痫发作，无副作用目标的前景。虽然我的培训使我具备了解决这些问题并成为一名成功的独立研究人员所需的许多工具，但通过K99获得的进一步培训提供了关键的补充。具体来说，K99将提供1)新技术培训，2)公开演讲培训，3)改进的合作网络，4)额外的教学经验，以及5)资金和拨款写作培训。K99部分提供的额外培训和经验，加上我之前的经验，将使我能够建立一个成功的、独立的实验室，致力于解决健康和疾病中大脑结构内部和跨大脑结构的神经网络的基本问题。

DESCRIPTION (provided by applicant): Epilepsy is a condition of recurrent seizures. In the US alone, there are nearly 500 new cases of epilepsy diagnosed every day, and up to 50,000 epilepsy related deaths annually. Temporal lobe epilepsy is the most common form of epilepsy in adults, and is associated with cognitive decline. For over 40% of patients, seizures are not controlled with current treatment options, and systemic anti-epileptic drugs can have major, negative side-effects. New treatment options are needed. On-demand optogenetics, with real-time, seizure detection triggering the delivery of light to the hippocampus (a key brain structure in temporal lobe epilepsy), can stop spontaneous seizures in a mouse model of temporal lobe epilepsy. These techniques also provide a unique opportunity to investigate the networks critically involved in seizures. This proposal examines the role of cerebellar-hippocampal interactions during seizures and hippocampal-dependent cognition, using on- demand optogenetics, in vivo juxtacellular recordings, and behavioral testing with the intrahippocampal kainate mouse model of temporal lobe epilepsy. By recognizing the ability of the cerebellum to inhibit seizures, and identifying mechanisms through which this is mediated, we not only gain insight into seizures, but also achieve new therapeutic targets and strategies for treating this prevalent and serious disorder. Candidate and Career Summary I am interested in networks and neuronal diversity, and the roles of these in physiological processes and disease. My career goals include becoming an independent researcher, studying epilepsy and disorders which may provide additional insight into epilepsy. Key questions remain in epilepsy research, including what are the key networks and conditions involved in initiating, sustaining, propagating, terminating, and potentially suppressing temporal lobe seizures. By improving our understanding of these, we improve the prospects of someday reaching the goal of no seizures, no side effects, for all epilepsy patients. While my training has equipped me with many of the tools necessary for addressing these questions and becoming a successful independent researcher, the further training received through this K99 provides key additions. Specifically, this K99 will provide 1) training in new techniques, 2) public speaking training, 3) an improved network for collaborations, 4) additional teaching experience, and 5) funding and grant writing training. This additional training and experience provided by the K99 portion, combined with my prior experience, will allow me to establish a successful, independent laboratory working to address fundamental questions of neuronal networks, within and across brain structures, in health and disease.