Serotonin neurons in arousal, epilepsy and SUDEP

描述(由申请人提供)：这个有指导的临床科学家研究职业发展奖旨在促进候选人作为一名独立科学家的职业生涯，同时研究皮质激活的5-羟色胺能机制，因为它们可能与睡眠-唤醒调节和癫痫有关。大脑延髓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，可以感知血液二氧化碳(CO2)浓度和pH的变化。在延髓中，5-羟色胺神经元调节呼吸以响应二氧化碳浓度或pH的变化。中脑5-羟色胺神经元对化学药物敏感的原因尚不清楚；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。由于5-羟色胺参与睡眠觉醒调节、呼吸控制和癫痫易感性，5-羟色胺神经元功能障碍被认为是癫痫猝死(SUDEP)的病理生理基础，SUDEP是一种导致过早死亡的破坏性疾病。到目前为止，研究SUDEP的动物模型还很少。这项研究计划试图了解5-羟色胺神经元在癫痫发作后睡眠觉醒和呼吸调节中的作用，特别是作为中枢化学感受器的作用。在此过程中，还将阐明二氧化碳唤醒反应中特定的5-羟色胺机制。在两个不同的基因改变的小鼠品系中，将使用各种解剖学、外科、电生理和行为技术，在这两个品系中，5-羟色胺神经元要么出生时就不存在，要么在以后的生活中急剧沉默。在理想情况下，拟议工作的完成将导致改善小岛屿发展中国家和南欧小岛屿发展中国家风险人群的预防措施，并防止过早死亡。候选人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。在职业发展方面，这个导师和顾问团队将继续支持候选人在耶鲁医学院神经病学系内开发一个独立的研究计划，与癫痫发作后睡眠和觉醒的调节以及意识的调节有关。作为这个指导奖的一部分，通过课程作业、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把候选人带入他的独立神经科学家的职业生涯。

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.