A critical period of sleep required for normal brain development

描述（由申请人提供）：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。据推测，早期发育睡眠对正常的大脑模式有影响，而关键时期的睡眠障碍会对人类产生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，以及在发育中的动物中是什么机制控制了过度睡眠。本研究利用强大的黑腹果蝇模型系统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项目，并具体解决了2011年NIH睡眠障碍研究计划的目标，包括：1)阐明易受睡眠不足影响的神经发育和突触功能受损的分子病理生理机制和窗口；2)确定易受睡眠不足影响的发育时期的睡眠障碍在正常大脑发育轨迹中赋予风险的过程。候选人：Matthew Kayser在宾夕法尼亚大学获得神经科学博士和医学博士学位，并在那里完成了精神病学实习。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，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接受培训。这个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，而且

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.