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成为一名独立的科学家，同时研究皮层激活的血清素能机制，因为它们可能与睡眠-觉醒调节和癫痫有关。脑髓质和中脑中含有神经递质5-羟色胺（5-HT）的神经元是中枢化学感受器，能感知血液中二氧化碳（CO2）浓度和ph的变化。在髓质中，5-HT神经元根据二氧化碳浓度或ph的变化调节呼吸。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-羟色胺也与癫痫有关。考虑到睡眠-觉醒调节、呼吸控制和癫痫易感性，5-HT神经元功能障碍被认为是癫痫猝死（SUDEP）的病理生理学基础，这是一种导致过早死亡的毁灭性疾病。迄今为止，研究猝死症的动物模型还很缺乏。本研究计划旨在了解5-HT神经元的作用，特别是其作为中枢化学感受器的能力，在癫痫发作后调节睡眠-觉醒和呼吸。在此过程中，5-羟色胺在二氧化碳唤醒反应中的具体机制也将被阐明。各种解剖、外科、电生理和行为技术将被应用于两种不同的基因改变的小鼠系，其中5-HT神经元要么从出生时就缺失，要么在以后的生活中急剧沉默。理想情况下，完成拟议的工作将导致改善小岛屿发展中国家和突发猝死症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组优秀的导师和顾问，他们将指导实验设计，实验执行和结果分析。在职业发展方面，该导师和顾问团队将继续支持候选人在耶鲁大学医学院神经内科开展独立的研究项目，该项目与睡眠和觉醒的调节以及癫痫发作后的意识调节有关。通过课程、研讨会和国家会议获得的外科、行为和电生理技术方面的专业知识将使候选人成为一名独立的神经科学家。

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.