Dissecting hypothalamic pathways for seizure control

剖析控制癫痫发作的下丘脑通路

• 批准号: 10429492
• 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 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429492
• 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 (Brain); 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; Resources; Role; Seizures; Source; Specificity; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Thalamic structure; TimeLine; Training; Transgenic Mice; Translations; Universities; Work; base; calbindin; career development; cell type; cingulate cortex; clinical translation; clinically relevant; density; entorhinal cortex; experience; experimental study; in vivo; in vivo calcium imaging; kainate; miniaturize; neural network; neuroregulation; novel therapeutics; optogenetics; programs; recruit; relating to nervous system; support network; technique development; 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个人中就有一人在一生中的某个时候经历过癫痫，而颞叶癫痫是最常见的