On-demand optogenetic cerebellar intervention for temporal lobe epilepsy

项目摘要 研究综述 癫痫是一种反复发作的疾病。仅在美国，就有近500例新的癫痫病例 每天都被诊断出来，每年有多达50，000例癫痫相关死亡。颞叶癫痫是最常见的 成人癫痫的常见形式，与认知能力下降有关。超过40%的患者， 目前的治疗方案不能控制癫痫发作，全身性抗癫痫药物可能具有主要的， 负面的副作用需要新的治疗选择。按需光遗传学，具有实时，捕获 检测触发光传递到海马体（颞叶癫痫的关键大脑结构）， 可以阻止颞叶癫痫小鼠模型的自发性癫痫发作。这些技术还提供了 这是一个独特的机会，可以调查在缉获中起关键作用的网络。本提案审查了 癫痫发作和海马依赖性认知过程中小脑-海马相互作用的研究， 需要光遗传学、体内脑细胞记录和海马内红藻氨酸盐行为测试 颞叶癫痫小鼠模型。通过认识到小脑抑制癫痫发作的能力， 通过识别介导这一过程的机制，我们不仅可以深入了解癫痫发作， 新的治疗靶点和治疗这种流行和严重疾病的策略。 候选人和职业概述 我感兴趣的网络和神经元的多样性，以及这些在生理过程中的作用， 疾病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， 可以提供对癫痫的进一步了解。癫痫研究中的关键问题仍然存在，包括 涉及启动、维持、传播、终止和潜在 抑制颞叶癫痫发作通过提高我们对这些的理解，我们改善了 总有一天会达到所有癫痫患者都不会发作，没有副作用的目标。虽然我的训练 为我提供了许多必要的工具来解决这些问题，并成为一个成功的 独立研究员，通过K99接受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） 合作，4）额外的教学经验，和5）资金和赠款写作培训。该附加 K99部分提供的培训和经验，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，致力于解决神经元的基本问题， 网络，在大脑结构内部和之间，在健康和疾病中。

PROJECT SUMMARY Research Summary 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.