Dissecting hypothalamic pathways for seizure control

剖析控制癫痫发作的下丘脑通路

• 批准号: 10590683
• 负责人: Jordan Stewart Farrell
• 金额: $ 11.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590683
• 关键词: Adult; Anterior; Anterior Nuclear Group; Automobile Driving; Back; Biological; Brain; Cell Nucleus; Cells; Chronic; Clinical Trials; Collaborations; Coupled; Data; Deep Brain Stimulation; Devices; Drug resistance; Electrophysiology (science); Epilepsy; Event; Excision; Failure; Fiber; Focal Seizure; Focused Ultrasound; Future; Goals; Grant; High Frequency Oscillation; Hippocampus; Hypothalamic structure; Innovative Therapy; Knowledge; Label; Laboratories; Life; Light; Mammillary body structure; Medial; Memory; Mentors; Modality; Modeling; Mus; Neurons; Neurosciences; Neurotensin; Operative Surgical Procedures; Output; Partial Epilepsies; Pathologic; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Physiological Processes; Pilocarpine; Play; Positioning Attribute; Postdoctoral Fellow; Recurrence; Refractory; Research; Research Training; Resected; Resources; Role; Seizures; Source; Specificity; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Thalamic structure; Training; Transgenic Mice; Translations; Universities; Work; calbindin; career development; cell type; cingulate cortex; clinical translation; clinically relevant; density; entorhinal cortex; epileptiform; experience; experimental study; in vivo; in vivo calcium imaging; kainate; miniaturize; neural; neural network; neuroregulation; novel therapeutics; optogenetics; postsynaptic; programs; recruit; support network; technique development; timeline; tool; ultrasound

One in 26 people experience epilepsy at some point in their life and temporal lobe epilepsy is the most common adult focal epilepsy. New and innovative therapies are required to treat the many cases of temporal lobe epilepsy that are poorly controlled with conventional medications. Ideally, treatments should be based on a detailed understanding of the mechanisms that give rise to seizures, but these biological mechanisms are poorly understood. The conventional approach is to surgically remove the seizure “focus” in attempts to alleviate seizures, but identifying the focus is challenging. Even in cases when the focus is ostensibly clear, surgery may not prevent seizures. An alternative hypothesis is that even classically focal epilepsies, such as temporal lobe epilepsy, rely on more distributed brain networks. One such network that is well-positioned to support seizures is the Papez circuit, which embeds the hippocampus, a classic seizure focus, in a recurrent excitatory network. Preliminary work demonstrates that the medial mammillary body, the hypothalamic node of this circuit, drives synchronous network events in the hippocampus and highlights a potential role as an external controller for pathologically synchronous states (i.e., epileptiform events). Using transgenic mouse lines and cell-type-specific tools, two divergent pathways from the medial mammillary body will be investigated to determine 1) how seizure activity spreads through these pathways, 2) whether these pathways are necessary and sufficient for seizure activity, and 3) if targeted, non-invasive neuromodulation with ultrasound can control seizure activity. Completing this grant will advance our understanding of the mechanisms that generate seizure activity and take a first step towards translation using a clinically relevant treatment modality. The candidate's long-term goal is to establish an independent research program that sheds light on the organization and function of networks that support physiological processes (e.g., memory) and pathological seizures. To attain this goal, the candidate has outlined a comprehensive, personalized program that identifies plans for career development in research training, neuroscience knowledge, technique development, grantsmanship, scientific management, and others. This training plan outlines a pathway to independence (i.e., from postdoc to establishing their own laboratory) that has a realistic timeline and is supported excellent resources at Stanford University, collaboration, and an established mentor with extensive experience relevant to this goal.

每26个人中就有一个人在一生中的某个时候经历过癫痫，其中最常见的是颞叶癫痫 成人局灶性癫痫。需要新的和创新的疗法来治疗许多颞叶癫痫病例 用常规药物控制不佳。理想情况下，治疗应该基于详细的 对引起癫痫发作的机制的了解，但这些生物学机制很差 明白了。传统的治疗方法是通过外科手术移除癫痫的“病灶”，试图缓解 癫痫发作，但确定病灶是具有挑战性的。即使在病灶表面清晰的情况下，手术也可能 而不是防止癫痫发作。另一种假说是，即使是经典的局灶性癫痫，如颞叶 癫痫，依赖于更多的分布式大脑网络。一个这样的网络处于有利地位，可以支持癫痫发作 帕佩兹环路，它嵌入了海马体，这是一个经典的癫痫发作焦点，在一个经常性的兴奋网络中。 初步研究表明，内侧乳头体，这个回路的下丘脑节点，驱动 海马体中的同步网络事件，并突出了作为外部控制器的潜在作用 病理同步状态(即癫痫样事件)。使用转基因小鼠品系和特定细胞类型 工具，内侧乳头体的两条不同路径将被调查以确定1)如何癫痫发作 活动通过这些途径传播，2)这些途径是否对癫痫发作是必要的和充分的 3)如果有针对性，超声波的非侵入性神经调节可以控制癫痫发作的活动。正在完成 这笔赠款将促进我们对癫痫发作活动产生机制的了解，并迈出第一步 使用临床上相关的治疗方式进行翻译。候选人的长期目标是建立 一项独立研究计划，旨在了解支持以下服务的网络的组织和功能 生理过程(如记忆)和病理性癫痫发作。为了实现这一目标，候选人概述了 一个全面、个性化的计划，确定研究培训中的职业发展计划， 神经科学知识、技术发展、勇气、科学管理等。这 培训计划勾勒出了一条独立的道路(即从博士后到建立自己的实验室)， 有一个现实的时间表，并得到斯坦福大学的出色资源、协作和 具有与此目标相关的丰富经验的可靠导师。