Serotonin neurons in arousal, epilepsy and SUDEP

唤醒、癫痫和 SUDEP 中的血清素神经元

• 批准号: 8849987
• 负责人: Gordon Frank Buchanan
• 金额: $ 17.43万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-03 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849987
• 关键词: Acidosis; Animal Model; Arousal; Award; Behavioral; Benchmarking; Birth; Blood; Brain; Breathing; Carbon Dioxide; Cause of Death; Cessation of life; Chemoreceptors; Clinical; Conscious; Data; Disease; Dorsal; Electroconvulsive Shock; Epilepsy; Experimental Designs; Functional disorder; General Population; Generalized seizures; HTR2A gene; High Pressure Liquid Chromatography; Hydroxyindoleacetic Acid; Hypercapnia; Hypothalamic structure; Impairment; Individual; K-Series Research Career Programs; Label; Lateral; Lead; Length; Lesion; Life; Measures; Mediating; Mental Depression; Mentors; Microdialysis; Microinjections; Midbrain structure; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurology; Neurons; Neurotransmitters; Operative Surgical Procedures; Patients; Populations at Risk; Predisposition; Public Health; Recovery; Recruitment Activity; Regulation; Relative (related person); Research; Research Proposals; Respiration; Respiratory physiology; Risk; Risk Factors; Role; Scientist; Seizures; Serotonin; Serotonin Receptors 5-HT-3; Sleep; Staging; Sudden Death; Sudden infant death syndrome; Techniques; Thalamic structure; Time; Wakefulness; Whole Body Plethysmography; Work; career; career development; design; extracellular; hypocretin; improved; medical schools; mortality; neurotransmission; premature; prevent; programs; prophylactic; receptor; research study; respiratory; response; sleep epilepsy; sleep regulation; stimulus sensitivity; symposium

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.

描述（由申请人提供）：这一指导的临床科学家研究职业发展奖旨在使候选人成为独立科学家的职业，同时研究皮质激活的血清素能机制，因为它们可能与睡眠效果调节和癫痫病有关。含有神经递质5-羟色胺（5-HT）的髓质和大脑中间脑中的神经元是中央化学感受器，感知血液二氧化碳（CO2）浓度和pH的变化。在髓质中，5-HT神经元对二氧化碳浓度变化或pH的变化进行调节。中脑5-HT神经元的化学敏感性的原因尚不清楚。但是，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。鉴于参与睡眠效果调节，呼吸控制和癫痫敏感性，已经提出了5-HT神经元功能障碍是为了构成癫痫病（SUDEP）突然意外死亡的病理生理学，这是一种毁灭性疾病，导致过早死亡。迄今为止，动物模型缺乏研究SUDEP。这项研究建议旨在了解5-HT神经元的作用，尤其是其作为中央化学感受器的能力，在癫痫发作后调节睡眠吸收和呼吸中的作用。在执行此操作时，还将阐明对CO2的唤醒反应中的特定5-HT机制。各种解剖学，外科，电生理和行为技术将采用两种不同的遗传改变的小鼠系，其中5-HT神经元在出生中不存在，或者可以在以后的生活中急剧沉默。理想情况下，提议的工作的完成将改善有小岛和SUDEP风险的个体的预防措施，并防止过早死亡。候选人招募了一群出色的导师和顾问，这些团体将指导实验设计，实验执行和结果分析。对于职业发展，该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在神经病学系中制定了一项独立的研究计划，与癫痫发作后的睡眠和清醒有关，并调节意识。通过课程，研讨会和民族会议作为该指导奖的一部分，通过课程，研讨会和民族会议获得的手术，行为和电生理技术获得的专业知识将使候选人成为独立的神经科学家的职业。

项目成果

Effect of serotonin transporter genotype on carbon dioxide-induced fear-related behavior in mice.

• DOI: 10.1177/0269881120959611
• 发表时间: 2020-12
• 期刊: Journal of psychopharmacology (Oxford, England)
• 作者: Leibold NK;van den Hove D;Weidner MT;Buchanan GF;Steinbusch HW;Lesch KP;Schruers KR
• 通讯作者: Schruers KR