Serotonin neurons in arousal, epilepsy and SUDEP

描述（由申请人提供）：该指导临床科学家研究职业发展奖旨在推动候选人作为独立科学家的职业生涯，同时研究皮质激活的肾上腺素能机制，因为它们可能与睡眠-觉醒调节和癫痫有关。含有神经递质5-羟色胺（5-HT）的脑的髓质和中脑中的神经元是感觉血液二氧化碳（CO2）浓度和pH的变化的中枢化学感受器。在髓质中，5-HT神经元响应于CO2浓度或pH的变化而调节呼吸。然而，我们现在有数据表明它介导了对二氧化碳浓度升高的唤醒反应。5-HT也与癫痫有关。由于涉及睡眠-觉醒调节、呼吸控制和癫痫易感性，5-HT神经元功能障碍已被提出为癫痫中突然意外死亡（SUDEP）的病理生理学基础，SUDEP是一种导致过早死亡的毁灭性疾病。迄今为止，缺乏研究SUDEP的动物模型。这项研究计划旨在了解5-HT神经元的作用，特别是它们作为中枢化学感受器的能力，在癫痫发作后睡眠-觉醒和呼吸的调节中的作用。在此过程中，还将阐明对CO2的唤醒反应中的特定5-HT机制。各种解剖，外科手术，电生理和行为技术将采用两种不同的基因改变的小鼠品系，其中5-HT神经元要么从出生时就不存在，要么可以在以后的生活中急剧沉默。完成拟议的工作将理想地导致改善对SIDS和SUDEP风险个体的预防措施，并防止过早死亡。候选人已经招募了一批优秀的导师和顾问，他们将指导实验设计，实验执行和结果分析。对于职业发展，这个导师和顾问团队将继续支持候选人，因为他在耶鲁大学医学院神经病学系内开发了一个独立的研究项目，该项目与睡眠和觉醒的调节以及癫痫发作后意识的调节有关。通过课程、研讨会和全国会议获得的外科、行为和电生理技术方面的专业知识作为该指导奖的一部分，将使候选人成为独立的神经科学家。

DESCRIPTION (provided by applicant): This mentored clinical scientist research career development award is designed to advance the candidate toward a career as an independent scientist while investigating serotonergic mechanisms of cortical activation as they may pertain to sleep-wake regulation and epilepsy. Neurons in the medulla and midbrain of the brain that contain the neurotransmitter serotonin (5-HT) are central chemoreceptors that sense changes in blood carbon dioxide (CO2) concentration and pH. In the medulla, 5-HT neurons modulate breathing in response to changes in CO2 concentration, or pH. The reason for the chemosensitivity of midbrain 5-HT neurons was not known; however, we now have data to suggest it mediates an arousal response to elevated CO2 concentrations. 5-HT has also been implicated in epilepsy. Given the involvement with sleep-wake regulation, respiratory control and seizure susceptibility, 5-HT neuron dysfunction has been proposed to underlie the pathophysiology of sudden unexpected death in epilepsy (SUDEP), a devastating disease that results in premature death. To date there is a paucity of animal models to study SUDEP. This research proposal seeks to understand the role of 5-HT neurons, especially in their capacity as central chemoreceptors, in the regulation of sleep-wakefulness and breathing following a seizure. In doing this the specific 5-HT mechanisms in the arousal response to CO2 will also be elucidated. A variety of anatomical, surgical, electrophysiological and behavioral techniques will be employed in two different genetically altered mouse lines in which 5-HT neurons are either absent from birth or can be acutely silenced later in life. Completion of the proposed work will ideally lead to improved prophylactic measures in individuals at risk for SIDS and SUDEP and prevent untimely death. The candidate has recruited an outstanding group of mentors and advisors that will guide experimental design, execution of experiments, and analysis of results. For career development, this mentor and advisor team will continue to support the candidate as he develops an independent research program within the Department of Neurology at the Yale School of Medicine relevant to the regulation of sleep and wakefulness and the regulation of consciousness following seizures. Expertise gained in surgical, behavioral, and electrophysiological techniques through coursework, seminars and national conferences as part of this mentored award will carry the candidate into his career as an independent neuroscientist.