Neural circuit mechanisms controlling seizures

控制癫痫发作的神经回路机制

基本信息

批准号：
10383710
负责人：
Quynh Anh Nguyen
金额：
$ 12.23万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383710
关键词：
Acute Adult Advisory Committees Anatomy Animal Model Animals Antiepileptic Agents Area Award Behavior Biological Markers Brain imaging Brain region Calcium Cells Chronic Chronic Phase Cognitive Cognitive deficits Contralateral Detection Development Disease Early Intervention Educational process of instructing Electrophysiology (science)Environment Epilepsy Epileptogenesis Event Evolution Frequencies Functional disorder Gene Expression Profiling Generations Genetic Goals Grant High Frequency Oscillation Hippocampus (Brain)Human Image Impaired cognition Injections Intervention Investigation Ipsilateral Knock-out Knockout Mice Label Lead Learning Light Light Exercise Mediating Memory Memory impairment Methods Modeling Molecular Molecular Genetics Molecular Profiling Mus Nature Neurons Pathologic Patients Performance Pharmacotherapy Phase Play Population Pyramidal Cells Recurrence Research Personnel Research Training Resistance Resources Role Seizures Signal Transduction System Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Intervention Tissue imaging Training Transgenic Mice Work Writing career career development cellular targeting comorbidity effective therapy efficacious treatment experience genetic approach hippocampal sclerosis human model in vitro activity in vivo kainate knockout gene mouse model nervous system disorder neural circuit neuronal circuitry new therapeutic target novel optogenetics prevent receptor side effect skills social success tool tool development two-photon

项目摘要

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is associated with significant cognitive decline. In over 40% of TLE cases, seizures are not controlled with current treatment options and systemic anti-epileptic drug administration can have major negative side effects, prompting the need for more effective therapies. However, the cellular and circuit mechanisms underlying TLE are not yet understood due to the inherent challenges of studying chronic spontaneous seizures which typically occur within a relatively short temporal window, often on a timescale of seconds to minutes. Using a recently developed molecular tool, which integrates light and calcium to label active cells within a short temporal window, along with a closed-loop system for seizure detection and light delivery, preliminary results identified a distinct cluster of cells within the hippocampus prominently active during seizures. Additional preliminary work identifies this region as also involved during interictal epileptiform events, suggesting it is a critical control node in the development of seizures. This proposal will employ two different models of TLE, a recently developed focal genetic knockout model and the intrahippocampal kainite model, to dissect the role of this ensemble and 1) Determine its involvement in both interictal and ictal activity in chronically epileptic animals; 2) Determine whether optogenetic inhibition of these cells during seizures can control chronic spontaneous seizures and its associated cognitive comorbidities using a transgenic mouse line that provides access to this distinct population of cells; and 3) Determine whether early intervention in this region can prevent the progression of epilepsy and its associated cognitive comorbidities. The candidate has assembled an Advisory Committee comprised of Gyorgy Buzsaki, Liqun Luo, and Alice Ting to support the acquisition of additional training in closed-loop control of neuronal oscillations, cleared tissue imaging and gene expression analysis, and molecular tool development. In addition, the candidate proposes a personalized plan for career development comprised of additional experience in grant writing, teaching, and scientific management to facilitate success as an independent researcher. The candidate’s long-term goal is to develop a career as an independent neuroscientist utilizing multi-scale investigation at the level of molecules, cells, circuits, and behavior to understand mechanisms of neuronal function and their dysfunction in neurological disorders such as epilepsy. Completion of the proposed study will advance the field by 1) Establishing a previously unknown relationship between interictal and ictal activity; 2) Identifying the therapeutic potential of intervention in a previously unexplored area of the hippocampus to control seizures and associated cognitive deficits; and 3) Identify seizure-specific cellular ensembles for further study. The training period afforded by the K99/R00 award will allow the candidate to develop a powerful set of skills and resources to use in her independent career and the interdisciplinary nature at Stanford provides the ideal environment for the candidate to carry out the research and training plan successfully.

颞叶癫痫（TLE）是与认知相关的最常见的epilt形式。细胞和电路机制在固有的挑战自发癫痫发作中尚未发生，这些癫痫发作通常在相对短的时间窗口内发生，通常是在秒到几分钟内。初步的结果在癫痫发作中鉴定海马中的一个明显活性。癫痫动物的间歇性动物和截肢动物；候选人组装了一个由Zsaki，Laqu Luo和Alice Ting的咨询，以获取对神经元振荡的额外训练环控制，清除的组织成像和基因分析，以及分子工具的开发。批准，教学和科学管理方面的经验，以促进候选人的长期职业。为了了解神经元功能的机制，例如癫痫病，例如1）识别在先前未开发的海马癫痫发作和相关认知缺陷的训练期间，识别出治疗性的潜在。 K99/R00 Award将候选人开发一套有力的技能和资源，以便在她的独立职业中使用，而斯坦福大学的跨学科性质为候选人提供了the搜索的环境，并成功地进行了Thearch并成功计划。