A critical period of sleep required for normal brain development

描述(申请人提供)：几乎所有的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起着保守的作用。早期发育睡眠被认为在正常的大脑模式中起作用，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，尚不清楚大脑的正常结构成熟是否需要睡眠，以及发育中的动物中控制过度睡眠的机制是什么。这项建议利用强大的模型系统黑腹果蝇来确定睡眠早期发育中断如何影响神经回路形成和成年行为。该项目直接参与了NINDS的系统和认知神经科学计划，并专门针对2011年NIH睡眠障碍研究计划的目标，包括：1)阐明与神经发育和突触功能受损有关的睡眠不足的分子病理生理机制和易感性窗口，以及2)确定发育脆弱时期的睡眠障碍导致正常大脑发育轨迹中的风险的过程。候选人：Matthew Kayser在宾夕法尼亚大学获得神经科学博士和博士学位，并在那里完成精神病学住院医师。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，在致力于了解睡眠和昼夜节律的遗传和神经生物学底物的实验室接受培训。这项提议建立在他对神经发育的既定兴趣之上，将产生新的科学结果，此外 为应聘者提供关键培训。申请者的长期目标是成为一名由R01资助的独立研究员，研究生命早期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：凯瑟博士的导师阿米塔·塞格尔博士提供了无与伦比的专业知识。塞加尔博士以利用果蝇研究睡眠和昼夜节律而闻名于世。15年来，她一直得到HHMI和NIH的资助，并为本提案中描述的工作提供了广泛的资源。西格尔博士在指导方面也有良好的记录。申请者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，以及来自多样化和专注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，他正被积极招募为终身教职助理教授。研究：初步结果表明，果蝇的睡眠个体发育受促进觉醒的多巴胺能活动的发育延迟所控制，我们已经在幼蝇中发现了控制睡眠的特定的多巴胺能神经回路。只有在关键的发育窗口期，该回路的过度兴奋才会导致睡眠缺失，从而导致成人社交行为的持久缺陷。这些行为缺陷被追踪到参与信息素依赖的求偶活动的单个嗅觉小球。这个肾小球独特地显示了幼龄果蝇广泛的睡眠依赖生长，这表明大脑快速生长的区域在生命早期最容易受到睡眠干扰。此外，我们假设，肾小球的生长增强反映了更高的突触增加速度。这项建议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)表明关键时期睡眠剥夺损害了支撑成人行为的正常发育程序，以及3)测试睡眠在突触形成中的作用。拟议中的科学研究，塞格尔博士的指导，以及候选人部门和咨询委员会的热情支持，将使凯瑟博士能够作为一名独立的内科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.