Dissecting hypothalamic pathways for seizure control

每26人中就有一人在一生中的某个时候经历过癫痫，颞叶癫痫是最常见的 成人局灶性癫痫需要新的和创新的疗法来治疗颞叶癫痫的许多病例 这些疾病用常规药物控制得很差。理想情况下，治疗应基于详细的 了解引起癫痫发作的机制，但这些生物学机制很差 明白传统的方法是手术切除癫痫发作的“病灶”， 癫痫发作，但确定重点是具有挑战性的。即使在病灶表面清楚的情况下，手术也可能 而不是预防癫痫另一种假设是，即使是典型的局灶性癫痫，如颞叶癫痫， 癫痫依赖于更分散的大脑网络。有一个这样的网络， 是帕佩兹回路，它将海马体（一个典型的癫痫发作部位）嵌入一个反复发作的兴奋性网络中。 初步工作表明，内侧乳头体，下丘脑节点的这一电路，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， 病理同步状态（即，癫痫样事件）。使用转基因小鼠品系和细胞类型特异性 工具，两个不同的途径，从内侧乳头体将被调查，以确定1）如何癫痫发作 活动通过这些途径传播，2）这些途径是否是癫痫发作所必需和充分的 活动，以及3）如果有针对性，使用超声的非侵入性神经调节可以控制癫痫发作活动。完成 这项拨款将促进我们对癫痫发作机制的理解， 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 一个独立的研究计划，揭示了网络的组织和功能，支持 生理过程（例如，记忆）和病理性癫痫发作。为了实现这一目标，候选人概述了 一个全面的，个性化的计划，确定在研究培训的职业发展计划， 神经科学知识，技术开发，granitarian，科学管理和其他。这 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）， 有一个现实的时间轴，并支持在斯坦福大学，合作和一个优秀的资源， 建立导师与相关的这一目标的丰富经验。

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.