Cerebellar computations in health and epilepsy

健康和癫痫中的小脑计算

• 批准号: 10524402
• 负责人: Martha L Streng
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524402
• 关键词: Acute; Address; Affect; Anatomy; Area; Attenuated; Behavior; Behavioral; Calcium; Cell Nucleus; Cerebellar Cortex; Cerebellum; Cerebral cortex; Cessation of life; Chronic; Cognitive deficits; Cues; Data; Disease; Dorsal; Electrophysiology (science); Epilepsy; Foundations; Functional disorder; Goals; Grant; Health; Hippocampus (Brain); Image; Impact Seizures; Impairment; Individual; Intervention; Kainic Acid; Laboratories; Lateral; Lead; Lesion; Literature; Medial; Methods; Modeling; Motor; Movement; Mus; Neurons; Outcome; Output; Pathway interactions; Patient-Focused Outcomes; Patients; Physiology; Population Dynamics; Prosencephalon; Purkinje Cells; Research; Research Personnel; Research Technics; Rewards; Rodent Model; Role; Seizures; Sensory; Solid; Somatosensory Cortex; Structure; Surface; Technical Expertise; Techniques; Temporal Lobe Epilepsy; Testing; Thalamic structure; Therapeutic Intervention; Training; United States; Viral; Water; Writing; attenuation; base; career; comorbidity; experience; improved; innovation; insight; interest; mouse model; neocortical; nervous system disorder; new therapeutic target; novel; optogenetics; recruit; response; skills; spatiotemporal; targeted treatment

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.

项目摘要 癫痫是一种以慢性自发性癫痫发作为特征的疾病，是第四大常见的神经系统疾病。 在美国，每27个人中就有1人患有这种疾病。除了癫痫本身，慢性 癫痫与认知缺陷、结构变化和毁灭性的负面后果有关。列作 在所有癫痫患者中，有一半的癫痫发作不能用目前的治疗方案控制。有一个 迫切需要揭示慢性癫痫如何影响整体功能，并提出新的途径， 治疗干预尽管传统上与癫痫无关，但小脑正在出现 作为癫痫发作网络中的潜在关键节点;癫痫的小脑结构改变与 合并症和不良后果，针对小脑的干预可以有效地减轻 颞叶癫痫小鼠模型中的海马癫痫发作。癫痫发作的这种双向影响 小脑和反之亦然清楚地概述了小脑区域作为癫痫的潜在关键角色， 然而，未知的确切作用对患者有重大影响。该提案利用了一种新的技术， 小脑皮质的中尺度成像，以探测不同的癫痫发作网络如何改变小脑活动， 以及确定靶向小脑输出是否可以减弱在结构以外的癫痫发作。 海马体。通过揭示小脑如何与不同的癫痫灶相互作用，我们不仅可以获得 关键的洞察癫痫发作和慢性癫痫对小脑功能的影响，但也可能 在不同癫痫的治疗中发现新的治疗调节靶点。 我的首要研究兴趣是了解小脑皮层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 研究小脑网络动力学以及在运动和非运动过程中与前脑结构的相互作用 行为，以及癫痫和癫痫发作。我以前的培训背景给了我坚实的基础 在电生理记录，行为分析，光遗传学操纵，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，本文中概述的培训 K99将使我掌握实验技术和分析策略的新技能，以表征细胞 和使用钙成像的网络动态。除了新的技术专长，这款K99还将为我提供 随着科学网络的扩大，实验室管理技能的提高，以及资助申请的增加， 专业知识结合我之前的经验，K99提供的额外培训和专业知识 提供了关键的补充，这将有助于我建立一个成功的，独立的实验室， 尖端研究技术，探索小脑计算及其对健康的具体贡献 行为和疾病。