Cerebellar computations in health and epilepsy

项目总结 癫痫，一种以慢性自发性癫痫为特征的疾病，是第四种最常见的神经系统疾病 在美国，每27个人中就有一个受到影响。除了癫痫本身，慢性 癫痫与认知缺陷、结构变化和破坏性的负面后果有关。对于AS 多达一半的癫痫患者，目前的治疗方案无法控制癫痫发作。有一个 迫切需要发现慢性癫痫是如何影响整体功能的，以及推进治疗的新途径 治疗性干预。尽管传统上与癫痫没有关联，但小脑正在出现 作为癫痫网络中一个潜在的关键节点；癫痫的小脑结构改变与此有关 有并发症和负面结果的，针对小脑的干预可以有效地减弱 小鼠颞叶癫痫模型中的海马区癫痫发作。癫痫发作的这种双向影响 小脑和小脑反之亦然，清楚地勾勒出小脑区域是癫痫的潜在关键因素，其 然而，未知的确切角色对患者具有重大影响。这项提议利用了一种新技术来 小脑皮质的中尺度成像，以探索不同的癫痫网络如何改变小脑活动，如 以及确定靶向小脑输出是否可以减轻在大脑皮质以外结构中引起的癫痫发作 海马体。通过揭示小脑如何与不同的癫痫灶相互作用，我们不仅将获得 对癫痫发作和慢性癫痫对小脑功能的影响的关键洞察，但也可能 在不同癫痫的治疗中发现治疗调节的新靶点。 我最主要的研究兴趣是了解小脑皮质执行的计算以及如何 它们有助于健康的行为和疾病。我的职业目标包括成为一名独立研究员 运动与非运动时小脑网络动力学及其与前脑结构相互作用的研究 行为，以及癫痫和癫痫发作。我以前的训练背景给了我坚实的基础 在电生理记录、行为分析、光遗传操作以及 癫痫的啮齿动物模型。然而，为了充分实现我的独立研究目标，在这篇文章中概述的培训 K99将使我在实验技术和分析策略方面掌握新的技能，以表征细胞 以及使用钙质成像的网络动力学。除了新的技术专长外，这款K99还将为我提供 扩大了科学网络，提高了实验室管理技能，并增加了拨款 专业知识。结合我以前的经验，K99提供的额外培训和专业知识 提供关键补充内容，帮助我建立一个成功的、独立的实验室， 探索小脑计算及其对健康的具体贡献的尖端研究技术 行为和疾病。

PROJECT SUMMARY Epilepsy, a condition characterized by chronic, spontaneous seizures, is the fourth most common neurological disorder, affecting nearly 1 in 27 individuals in the United States. In addition to the seizures themselves, chronic epilepsy is associated with cognitive deficits, structural changes, and devastating negative outcomes. For as many as half of all epilepsy patients, seizures are not controlled with current treatment options. There is an urgent need to uncover how chronic epilepsy impacts overall function as well as advance new avenues for therapeutic intervention. Despite not being traditionally associated with epilepsy, the cerebellum is emerging as a potentially critical node in the seizure network; cerebellar structural alterations in epilepsy are associated with comorbidities and negative outcomes, and interventions targeting the cerebellum can powerfully attenuate hippocampal seizures in a mouse model of temporal lobe epilepsy. This bi-directional influence of seizures on the cerebellum and vice versa clearly outline the cerebellum area as a potentially key player in epilepsy, whose yet unknown exact role carries major implications for patients. This proposal leverages a novel technique for mesoscale imaging of the cerebellar cortex to probe how diverse seizure networks alter cerebellar activity, as well as determine whether targeting cerebellar outputs can attenuate seizures arising in structures beyond the hippocampus. By uncovering how the cerebellum interacts with different seizure foci, we will not only gain critical insight into the impact of seizures and chronic epilepsy on cerebellar function, but also potentially uncover new targets for therapeutic modulation in the treatment of different epilepsies. My overarching research interest is to understand computations performed by the cerebellar cortex and how they contribute to healthy behavior and disease. My career goals include becoming an independent researcher studying cerebellar network dynamics and interactions with forebrain structures during motor and non-motor behavior, as well as epilepsy and seizures. My previous training background has given me a solid foundation in electrophysiological recordings, behavioral analyses, optogenetic manipulations, and the implementation of rodent models of epilepsy. However, to fully realize my independent research goals, the training outlined in this K99 will equip me with new skills in experimental techniques and analysis strategies to characterize cellular and network dynamics using calcium imaging. In addition to new technical expertise, this K99 will provide me with a broadened scientific network, improved laboratory management skills, and augmented grant writing expertise. Combined with my prior experience, the additional training and expertise provided by this K99 provides key additions that will help me establish a successful, independent laboratory incorporating innovative, cutting edge research techniques to explore cerebellar computations and their specific contributions to healthy behavior and disease.