Optogenetic and chemogenetic manipulations of striatal output pathways for seizure control

用于控制癫痫发作的纹状体输出通路的光遗传学和化学遗传学操作

• 批准号: 10004524
• 负责人: SAFWAN HYDER
• 金额: $ 3.28万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004524
• 关键词: Acute; Address; Affect; Amygdaloid structure; Anatomy; Animals; Anticonvulsants; Basal Ganglia; Brain region; Cell Nucleus; Cells; Choking; Chronic; Clinical; Code; Complex; Corpus striatum structure; Data Analyses; Data Set; Deep Brain Stimulation; Detection; Educational Curriculum; Efferent Pathways; Electroencephalography; Epilepsy; Failure; Fellowship; Fiber; Fire - disasters; Freedom; Globus Pallidus; Goals; Histologic; Invaded; Joints; Knowledge; Learning; Lesion; Location; Measures; Mediating; Medical; Mentors; Methods; Modeling; Monitor; Movement Disorders; National Research Service Awards; Nature; Neurology; Neurons; Operative Surgical Procedures; Output; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Physicians; Physiological; Rattus; Recurrence; Request for Proposals; Research; Residencies; Role; Scientist; Seizures; Services; Severities; Source; Standardization; Status Epilepticus; Substantia nigra structure; Sum; System; Techniques; Testing; Therapeutic Intervention; Time; Tonic - clonic seizures; Training; Training Programs; Translating; Update; Work; career development; improved outcome; in vivo; in vivo calcium imaging; interest; knowledge translation; neurophysiology; new therapeutic target; optogenetics; pre-clinical; pre-doctoral; presynaptic; recruit; restraint; skill acquisition

Project Abstract Deep brain stimulation for epilepsy is growing in use, and offers promise to patients for whom other treatments fail. Thus, identifying new targets for stimulation is of considerable clinical and translational interest. The basal ganglia (BG), which have been explored extensively for stimulation in movement disorders, also may be attractive targets for epilepsy. Preclincial studies show that modulating activity in BG nuclei such as the striatum and substantia nigra pars reticulata (SNpr) can potently suppress experimental seizures in acute models of epilepsy. However, the network mechanisms underlying this effect, and the degree to which this translates into models of chronic epilepsy remain unknown. This NRSA F30 proposal requests four years of support. During years 1 and 2, I plan to complete my doctoral thesis. The thesis will encompass the two aims presented in the following research plan that have been heavily updated to reflect my research progress since the submission of the original proposal. In aim 1, I will test the hypothesis that on-demand optogenetic silencing of the SNpr will suppress spontaneous seizures in chronically epileptic rats. In parallel, I will test the hypothesis that on-demand activation of the striatum will produce an equivalent suppression of spontaneous seizures. While these manipulations are well-studied in acute seizure models, these studies would be the first to evaluate the anticonvulsant potential of these regions in chronic epilepsy. During the course of this aim, I will learn the status epilepticus model of chronic epilepsy in rats and the set up of self-contained, automated systems to monitor their seizure activity. In aim 2, I will use fiber photometry to test the hypothesis that seizure activity progressively and differentially engages basal ganglia output pathways. I will also test the hypothesis that optogenetic manipulations that counteract pathological recruitment of striatal pathways will suppress seizures. The training in this aim includes learning the technical aspects of fiber photometry as well as coding and data analysis methods. Throughout the course of my doctoral research, I will continue to be trained in physiological and histological methods as well as general skills and career development. After I complete my thesis defense, I will complete my pre-doctoral medical training during years 3 and 4 of the fellowship period. Clinical training follows a standardized institutional curriculum. After this period of joint-degree training, I plan to apply to combined residency/fellowship tracks in physician-scientist training programs in neurology/epileptology. In sum, during the proposed fellowship period, I will gain expertise in cutting-edge techniques in neurophysiology concurrent with training in intellectual and practical career development. The work proposed will benefit the field by determining mechanisms of seizure propagation and restraint via basal ganglia nodes while also testing them as candidates for the management of chronic spontaneous epilepsies.

项目摘要 深部脑刺激治疗癫痫的应用越来越多，这为那些需要其他治疗方法的患者带来了希望。 治疗失败。因此，确定新的刺激目标具有相当大的临床和转化意义。 基底神经节（BG）已被广泛探索用于运动障碍的刺激，也可能 成为癫痫的有吸引力的目标。临床前研究表明，调节 BG 核的活性，例如 纹状体和黑质网状部 (SNpr) 可以有效抑制急性模型中的实验性癫痫发作 癫痫症。然而，这种效应背后的网络机制，以及这种效应转化的程度 慢性癫痫模型的研究尚不清楚。 这项 NRSA F30 提案需要四年的支持。在第一年和第二年，我计划完成我的 博士论文。本论文将涵盖以下研究计划中提出的两个目标 大量更新以反映自提交原始提案以来我的研究进展。 在目标 1 中，我将检验以下假设：SNpr 的按需光遗传学沉默会抑制 慢性癫痫大鼠的自发性癫痫发作。同时，我将测试按需激活的假设 纹状体的作用将产生对自发性癫痫发作的同等抑制。虽然这些操纵是 这些研究在急性癫痫模型中进行了充分研究，将是第一个评估其抗惊厥潜力的研究 慢性癫痫的这些区域。在这个目标的过程中，我将学习慢性癫痫持续状态模型 老鼠的癫痫症以及建立独立的自动化系统来监测其癫痫活动。 在目标 2 中，我将使用光纤光度测定法来检验癫痫发作活动逐渐进行且 差异性地参与基底神经节输出通路。我还将检验光遗传学的假设 对抗纹状体通路病理性募集的操作将抑制癫痫发作。培训内容 这一目标包括学习光纤光度测定的技术方面以及编码和数据分析 方法。 在我的博士研究过程中，我将继续接受生理学和 组织学方法以及一般技能和职业发展。完成论文答辩后，我将 在奖学金期间的第三年和第四年完成我的博士前医学培训。临床培训如下 标准化的机构课程。经过这段时间的联合学位培训，我打算申请联合学位 神经病学/癫痫病学医师科学家培训项目的住院医师/研究员课程。 总之，在拟议的研究金期间，我将获得以下领域尖端技术的专业知识： 神经生理学与智力和实践职业发展培训同时进行。拟议的工作 通过确定基底神经节节点的癫痫发作传播和抑制机制，将使该领域受益 同时还测试它们作为治疗慢性自发性癫痫的候选药物。