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 人中就有 1 人在一生中的某个阶段经历过癫痫，而颞叶癫痫是最常见的 成人局灶性癫痫需要新的创新疗法来治疗许多颞叶癫痫病例。 理想情况下，治疗应基于详细的药物治疗。 人们对引起癫痫发作的机制有了了解，但对这些生物学机制知之甚少 传统的方法是通过手术切除癫痫“病灶”以试图缓解。 癫痫发作，但确定病灶具有挑战性，即使病灶表面上很清楚，手术也可能会发生。 另一种假设是，即使是经典的局灶性癫痫，例如颞叶癫痫，也不能预防癫痫发作。 癫痫症依赖于更分散的大脑网络，这种网络能够很好地支持癫痫发作。 是帕佩斯环路，它将海马体（典型的癫痫灶）嵌入到周期性兴奋网络中。 初步工作表明，内侧乳头体（该回路的下丘脑节点）驱动 海马体中的同步网络事件，并强调了作为外部控制器的潜在作用 使用转基因小鼠系和细胞类型特异性的病理同步状态（即癫痫样事件）。 工具，将研究来自内侧乳头体的两条不同路径，以确定 1) 癫痫发作的方式 活动通过这些途径传播，2）这些途径对于癫痫发作是否是必要和充分的 3）如果有针对性，超声非侵入性神经调节可以控制癫痫发作活动。 这笔赠款将增进我们对产生缉获活动的机制的理解，并迈出第一步 使用临床相关的治疗方式进行翻译 候选人的长期目标是建立。 一个独立的研究项目，揭示了支持网络的组织和功能 为了实现这一目标，候选人概述了生理过程（例如记忆）和病理性癫痫发作。 一个全面的、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、技术开发、资助、科学管理等等。 培训计划概述了独立的途径（即从博士后到建立自己的实验室） 拥有现实的时间表，并得到斯坦福大学优秀资源、协作和支持 建立与此目标相关的丰富经验。