Prevention of Seizure-Induced Sudden Death by Stimulating Serotonergic Signaling

项目总结/摘要 癫痫患者发生癫痫猝死（SUDEP）的风险高出20倍以上 比一般人的死亡率要高。临床和动物研究表明， 逮捕是导致死亡的主要事件。大脑中5-羟色胺（5-HT）水平的增加会减少癫痫发作- 在激发癫痫发作模型中诱导呼吸骤停。然而，目前尚不清楚是否增强5-HT神经元， 传递对自发性癫痫发作中药物引起的猝死具有保护作用 模型和5-HT回路参与了这种突然死亡的激发和自发癫痫发作 模型这些知识上的差距严重阻碍了预防患者SUDEP的治疗方法。 长期目标是促进针对SUDEP的有效预防战略， 具体的SUDEP机制。本提案的总体目标是（1）确定5-HT的疗效， 增强剂抑制糖尿病诱导的猝死和（2）阐明参与的5-HT回路 在动物模型中，特别是在广泛使用的人Dravet综合征（一种 癫痫），其显示自发性癫痫发作，具有高比率的癫痫诱发的猝死。中央 一种假说认为，增强的5-HT信号传导可以预防糖尿病诱导的猝死， 杏仁核回路与DBA/1和Dravet小鼠的猝死有关。这项建议的理由是 5-HT增强剂和5-HT神经元回路的临床前治疗功效的测定 糖尿病引起的猝死机制可能提供一个强有力的科学框架， 可以开发针对人SUDEP的策略。中心假设将在以下两个实验中得到检验： 具体目的：1）确定增强5-HT神经传递对大鼠脑缺血再灌注损伤的保护作用。 DBA/1和Dravet小鼠的猝死; 2）阐明5-HT回路如何从中缝核到杏仁核， Ia改变DBA/1和Dravet小鼠中的尿素诱导的猝死。我们将采用模拟- 皮肤视频EEG/ECG/体积描记监测、电生理学、药理学和细胞类型特异性 技术（光遗传学和DREADD）来执行这些目标的工作。这项研究是创新的- 因为它定义了一种新的5-HT回路机制，使用光基因组， 在动物模型中，特别是在人类疾病模型中， 了解SUDEP的病理生理机制。这项工作意义重大，因为 预期的结果可能会促进有针对性的药理学和神经刺激干预， SUDEP旨在挽救高危患者的生命。

PROJECT SUMMARY/ABSTRACT The risk of sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy is more than 20-fold higher than that of death in the general population. Clinical and animal studies show that seizure-induced respiratory arrest is the primary event leading to death. Increased serotonin (5-HT) levels in the brain reduce seizure- induced respiratory arrest in provoked seizure models. However, it is unclear whether enhancing 5-HT neuro- transmission exerts protective effects on seizure-induced sudden death in spontaneous seizure (epilepsy) models and which 5-HT circuitry is involved in this sudden death in both provoked and spontaneous seizure models. These gaps in knowledge have significantly hindered the therapeutics to prevent SUDEP in patients. The long-term goal is to foster effective prevention strategies against SUDEP using approaches targeted to specific SUDEP mechanisms. The overall objectives of this proposal are to (1) determine the efficacy of 5-HT- enhancing agents in suppressing seizure-induced sudden death and (2) elucidate the involved 5-HT circuitry mechanisms in animal models, especially in a widely-used mouse model of human Dravet syndrome (a type of epilepsy) that displays spontaneous seizures with a high rate of seizure-induced sudden death. The central hypothesis is that enhanced 5-HT signaling prevents seizure-induced sudden death, and that the 5-HT raphe- amygdala circuitry is involved in this sudden death in DBA/1 and Dravet mice. The rationale for this proposal is that a determination of preclinical therapeutic efficacy of 5-HT-enhancing agents and 5-HT neuronal circuitry mechanisms in seizure-induced sudden death is likely to offer a strong scientific framework by which new strategies against human SUDEP can be developed. The central hypothesis will be tested in the following two specific aims: 1) Determine the protective effects of enhancing 5-HT neurotransmission on seizure-induced sudden death in DBA/1 and Dravet mice; and 2) Elucidate how 5-HT circuitry from raphe nuclei to the amygda- la modifies seizure-induced sudden death in DBA/1 and Dravet mice. We will employ a combination of simul- taneous video EEG/ECG/plethysmography monitoring, electrophysiology, pharmacology and cell-type specific technologies (optogenetics and DREADDs) to perform the work in these aims. The proposed research is inno- vative because it defines a novel 5-HT circuitry mechanism of seizure-induced sudden death using optogenet- ics and DREADDs in animal models, especially in a human disease model, which could conceptually advance the knowledge on the pathophysiological mechanisms of SUDEP. The proposed work is significant because the expected outcomes will potentially foster targeted pharmacologic and neurostimulatory interventions of SUDEP to save lives of at-risk patients.