A critical period of sleep required for normal brain development

大脑正常发育所需的关键睡眠期

• 批准号: 9120441
• 负责人: MATTHEW S KAYSER
• 金额: $ 19.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120441
• 关键词: Accounting; Acute; Address; Adult; Advisory Committees; Affinity Chromatography; Animals; Area; Arousal; Behavior; Behavioral; Biological Models; Brain; Brain region; Cells; Characteristics; Circadian Rhythms; Coupled; Courtship; Data; Development; Development Plans; Developmental Delay Disorders; Doctor of Philosophy; Dopamine; Dorsal; Drosophila genus; Drosophila melanogaster; Environment; Exhibits; Funding; Genes; Genetic; Goals; Grant; Growth; Health; Heterogeneity; Human; Impairment; Laboratories; Lead; Life; Link; Mediating; Mentors; Mentorship; Molecular; National Institute of Neurological Disorders and Stroke; Neurobiology; Neurologic; Neurons; Neurosciences; Olfactory Receptor Neurons; Pattern; Pennsylvania; Pheromone; Physicians; Play; Positioning Attribute; Postdoctoral Fellow; Process; Psychiatry; Recruitment Activity; Regulation; Research; Research Personnel; Residencies; Resources; Ribosomes; Risk; Role; Science; Scientific Inquiry; Scientist; Shapes; Signal Transduction; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Social Behavior; Sum; Synapses; System; Testing; Time; Training; Translating; Tyrosine 3-Monooxygenase; United States National Institutes of Health; Universities; Work; Writing; base; career; career development; circadian pacemaker; cognitive neuroscience; critical period; dopaminergic neuron; fly; improved; interest; neural circuit; neurobehavioral; neurodevelopment; neuropsychiatric disorder; neuropsychiatry; novel; novel strategies; olfactory bulb glomeruli; prevent; professor; programs; research study; sleep regulation; success; synaptic function; synaptogenesis; tenure track

DESCRIPTION (provided by applicant): Nearly all animals exhibit more sleep early in life, suggesting a conserved role for sleep during development. Early developmental sleep is hypothesized to have a role in normal brain patterning, and sleep disturbances during a critical period can have long-lasting neurobehavioral sequelae in humans. Yet, it is unknown whether sleep is required for normal structural maturation of the brain and what mechanisms control excess sleep in developing animals. This proposal utilizes the powerful model system Drosophila melanogaster to determine how early developmental disruptions in sleep impact neural circuit formation and adult behaviors. This project directly engages the Systems and Cognitive Neuroscience Program at NINDS, and specifically addresses goals of the 2011 NIH Sleep Disorders Research Plan, including: 1) elucidating molecular pathophysiological mechanisms and windows of vulnerability to sleep deficiency with respect to impaired neurological development and synaptic function, and 2) identifying the processes by which sleep disturbances during vulnerable periods of development confer risk in the trajectory of normal brain development. Candidate: Matthew Kayser received his MD and PhD in Neuroscience from the University of Pennsylvania, where he also completed Psychiatry residency. He is currently a postdoctoral fellow in the Center for Sleep and Circadian Neurobiology at Penn, pursuing training in a laboratory dedicated to understanding genetic and neurobiological substrates of sleep and circadian rhythms. This proposal builds on his established interest in neural development, will produce novel scientific results, and additionally provides critical training to the candidate. The applicant's long-term goal is to become an R01-funded independent investigator studying how sleep early in life sculpts brain circuits and can contribute to later neurobehavioral abnormalities. Environment: Dr. Kayser's mentor, Dr. Amita Sehgal, provides unparalleled expertise. Dr. Sehgal is world-renowned for her research on sleep and circadian rhythms utilizing Drosophila. She has been continuously funded by HHMI and NIH for over 15 years and offers extensive resources for the work described in this proposal. Dr. Sehgal also has a robust track record of mentorship. The applicant's career development plan entails rigorous training in sleep and Drosophila genetics/neurobiology, coursework in areas crucial to his success, and close guidance from a diverse and dedicated network of scientific advisors. In addition, Dr. Kayser has the full support of the Department of Psychiatry at Penn, to which he is being actively recruited as a tenure-track Assistant Professor. Research: Preliminary results show that sleep ontogeny in Drosophila is controlled by a developmental delay in wake-promoting dopaminergic activity, and we have identified a specific dopaminergic neural circuit controlling sleep in young flies. Sleep loss induced by hyperexcitation of this circuit only during a critical developmental window leads to lasting deficis in adult social behaviors. These behavioral deficits have been traced to a single olfactory glomerulus involved in pheromone-dependent courtship activity. This glomerulus uniquely displays extensive sleep-dependent growth in young flies, suggesting that rapidly growing regions of brain are most susceptible to sleep perturbations early in life. Moreover, we hypothesize that enhanced growth of this glomerulus reflects a higher rate of synapse addition. This proposal will build on preliminary data to 1) determine a mechanism controlling developmental changes in dopaminergic activity, 2) show that critical period sleep deprivation impairs a normal developmental program underlying adult behaviors, and 3) test a role for sleep in synaptogenesis. The proposed scientific inquiry, Dr. Sehgal's mentorship, and the enthusiastic support of the candidate's division and advisory committee will enable Dr. Kayser to launch a successful career as an independent physician-scientist.

描述（由申请人提供）：几乎所有动物在生命早期都会表现出更多的睡眠，这表明睡眠在发育过程中发挥着保守的作用。据推测，早期发育睡眠在正常的大脑模式中发挥作用，关键时期的睡眠障碍可能会给人类带来长期的神经行为后遗症。然而，尚不清楚睡眠是否是大脑正常结构成熟所必需的，以及发育中动物控制过度睡眠的机制是什么。该提案利用强大的模型系统果蝇来确定睡眠的早期发育中断如何影响神经回路的形成和成年行为。该项目直接参与 NINDS 的系统和认知神经科学项目，并具体解决 2011 年 NIH 睡眠障碍研究计划的目标，包括：1) 阐明分子病理生理学机制以及睡眠不足对神经发育和突触功能受损的脆弱性窗口，以及2）确定发育脆弱期睡眠障碍给正常大脑发育轨迹带来风险的过程。候选人：Matthew Kayser 在宾夕法尼亚大学获得神经科学医学博士和博士学位，并在那里完成了精神病学住院医师实习。他目前是宾夕法尼亚大学睡眠和昼夜节律神经生物学中心的博士后研究员，在致力于了解睡眠和昼夜节律的遗传和神经生物学基础的实验室接受培训。该提案建立在他对神经发育的既定兴趣之上，将产生新颖的科学成果，此外 为候选人提供关键培训。申请人的长期目标是成为一名由 R01 资助的独立研究者，研究生命早期的睡眠如何塑造大脑回路以及如何导致后来的神经行为异常。环境：Kayser 博士的导师 Amita Sehgal 博士提供了无与伦比的专业知识。 Sehgal 博士因其利用果蝇对睡眠和昼夜节律的研究而闻名于世。 15 年来，她一直受到 HHMI 和 NIH 的持续资助，并为本提案中描述的工作提供广泛的资源。 Sehgal 博士在指导方面也有着良好的记录。申请人的职业发展计划需要在睡眠和果蝇遗传学/神经生物学方面进行严格的培训，对他的成功至关重要的领域的课程作业，以及来自多元化和专门的科学顾问网络的密切指导。此外，凯瑟博士得到了宾夕法尼亚大学精神病学系的全力支持，他正在被积极招募为终身教授助理教授。研究：初步结果表明，果蝇的睡眠个体发育是由促进唤醒的多巴胺能活动的发育延迟控制的，并且我们已经确定了控制幼果蝇睡眠的特定多巴胺能神经回路。仅在关键的发育窗口期间由该回路过度兴奋引起的睡眠不足会导致成人社交行为的持久缺陷。这些行为缺陷可追溯到参与信息素依赖性求爱活动的单个嗅觉肾小球。这种肾小球在幼果蝇中独特地表现出广泛的睡眠依赖性生长，这表明大脑快速生长的区域最容易受到生命早期睡眠干扰的影响。此外，我们假设肾小球生长的增强反映了突触添加率的提高。该提案将建立在初步数据的基础上，以 1）确定控制多巴胺能活动发育变化的机制，2）表明关键期睡眠剥夺会损害成人行为的正常发育程序，3）测试睡眠在突触发生中的作用。拟议的科学探究、Sehgal 博士的指导以及候选人部门和咨询委员会的热情支持将使 Kayser 博士能够作为一名独立的医师科学家开启成功的职业生涯。