A critical period of sleep required for normal brain development

描述（由申请人提供）：几乎所有动物在生命早期都表现出更多的睡眠，这表明睡眠在发育过程中的作用是保守的。早期发育睡眠被假设在正常的大脑模式中起作用，在关键时期的睡眠障碍可能会对人类产生长期的神经行为后遗症。然而，目前尚不清楚睡眠是否是大脑正常结构成熟所必需的，以及什么机制控制发育中动物的过度睡眠。该建议利用强大的模型系统果蝇来确定睡眠中的早期发育中断如何影响神经回路形成和成年人的行为。该项目直接参与了NINDS的系统和认知神经科学计划，并具体解决了2011年NIH睡眠障碍研究计划的目标，包括：1）阐明与受损的神经发育和突触功能有关的易受睡眠不足影响的分子病理生理学机制和窗口，以及2）确定在发育的脆弱时期睡眠障碍对正常大脑发育的轨迹带来风险的过程。候选人：Matthew Kayser在宾夕法尼亚大学获得了神经科学的医学博士和博士学位，在那里他还完成了精神病学住院医师。他目前是宾夕法尼亚大学睡眠和昼夜神经生物学中心的博士后研究员，在一个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进行培训。这项建议建立在他对神经发育的既定兴趣之上，将产生新的科学成果，此外， 为候选人提供关键培训。申请人的长期目标是成为R 01资助的独立调查员，研究生命早期的睡眠如何塑造大脑回路，并可能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博士以她利用果蝇对睡眠和昼夜节律的研究而闻名于世。她一直由HHMI和NIH持续资助超过15年，并为本提案中描述的工作提供了广泛的资源。Sehgal博士也有一个强大的指导记录。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，在对他的成功至关重要的领域进行课程学习，以及来自多元化和专业的科学顾问网络的密切指导。此外，Kayser博士还得到了宾夕法尼亚大学精神病学系的全力支持，他正在积极招聘为终身助理教授。调研：初步结果表明，睡眠个体发育在果蝇是由发育延迟，促进觉醒的多巴胺能活性，我们已经确定了一个特定的多巴胺能神经回路控制睡眠的年轻苍蝇。只有在关键的发育窗口期间，由该回路的过度兴奋引起的睡眠丧失才会导致成年人社会行为的持久缺陷。这些行为缺陷已被追溯到一个单一的嗅觉小球参与信息素依赖的求偶活动。这种肾小球在幼蝇中独特地显示出广泛的睡眠依赖性生长，这表明大脑中快速生长的区域在生命早期最容易受到睡眠干扰。此外，我们推测，这肾小球的增长反映了较高的突触添加率。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性发育变化的机制，2）表明关键期睡眠剥夺损害了成年人行为的正常发育程序，3）测试睡眠在突触发生中的作用。Sehgal博士的指导，以及候选人的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生科学家开始成功的职业生涯。

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.