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例癫痫新病例被诊断出来，每年有多达50，000例癫痫相关死亡。颞叶癫痫是成年人中最常见的癫痫形式，并且与认知能力下降有关。对于超过40%的患者，癫痫发作无法通过当前的治疗方案得到控制，全身性抗癫痫药物可能具有重大的负面副作用。需要新的治疗选择。按需光遗传学，实时，癫痫发作检测触发光传递到海马体（颞叶癫痫的关键大脑结构），可以停止颞叶癫痫小鼠模型中的自发性癫痫发作。这些技术还为调查与缉获活动密切相关的网络提供了独特的机会。该提案使用按需光遗传学、体内海马细胞记录和使用颞叶癫痫的海马内红藻氨酸小鼠模型的行为测试来检查癫痫发作和海马依赖性认知期间小脑-海马相互作用的作用。通过认识小脑抑制癫痫发作的能力，并确定介导癫痫发作的机制，我们不仅可以深入了解癫痫发作，还可以实现新的治疗目标和策略来治疗这种普遍而严重的疾病。我对网络和神经元多样性以及它们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的研究人员，研究癫痫和疾病，这可能会为癫痫提供更多的见解。癫痫研究中的关键问题仍然存在，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，我们提高了有一天达到所有癫痫患者无癫痫发作，无副作用的目标的前景。虽然我的培训为我提供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接受的进一步培训提供了关键补充。具体来说，这个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，5）资金和赠款写作培训。K99部分提供的额外培训和经验，加上我以前的经验，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和跨大脑结构的神经元网络的基本问题。

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.