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的早期就表现出更多的睡眠，这表明在发育过程中睡眠起着保守的作用。假设早期发育睡眠在正常的脑部模式中起作用，并且在关键时期的睡眠障碍可以在人类中具有持久的神经行为后遗症。然而，尚不清楚大脑正常结构成熟以及哪些机制控制发育中的动物过度睡眠是尚不清楚的。该提案利用强大的模型系统果蝇Melanogaster来确定睡眠的早期发育破坏如何影响神经回路的形成和成人行为。该项目在NINDS上直接参与了系统和认知神经科学计划，并专门解决了2011年NIH睡眠疾病的目标研究计划，包括：1）阐明分子病理生理学机制和脆弱性弱化睡眠障碍的窗口，涉及神经学发育和突触功能受损的脑海中的脑海中的脑海中的发展，并且在脑海中遇到了不可接受的脑海中的开发，并在脑海中遇到了不利的脑海中的开发。候选人：马修·凯耶（Matthew Kayser）在宾夕法尼亚大学获得了神经科学的医学博士学位和博士学位，在那里他还完成了精神病学的居留权。他目前是宾夕法尼亚州睡眠和昼夜节律神经生物学中心的博士后研究员，在专门了解睡眠和昼夜节律的遗传和神经生物学基质的实验室中进行培训。这项建议是基于他对神经发展的既定兴趣，将产生新颖的科学结果，另外 向候选人提供重要的培训。申请人的长期目标是成为一名由R01资助的独立研究者，研究生命早期睡眠如何雕刻脑电路，并可以促成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博士因其对果蝇的睡眠和昼夜节律的研究而受到世界知名度。她一直由HHMI和NIH持续资助了15年以上，并为本提案中描述的工作提供了广泛的资源。 Sehgal博士还具有强大的指导记录。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，对他的成功至关重要的领域课程中进行严格的培训，以及来自多样化和专门的科学顾问网络的密切指导。此外，凯耶博士还得到了宾夕法尼亚州精神病学系的全力支持，他被积极招募为终身助理助理教授。研究：初步结果表明，果蝇中的睡眠个体受到促进唤醒多巴胺能活性的发育延迟控制，我们已经确定了控制年轻苍蝇睡眠的特定多巴胺能神经回路。仅在关键发展窗口中过度刺激该电路引起的睡眠损失会导致成人社会行为的持久缺陷。这些行为缺陷已被追溯到参与信息素依赖性求爱活动的单个嗅觉肾小球。这种肾小球独特地显示出年轻苍蝇的睡眠依赖性生长，这表明迅速增长的大脑区域最容易在生命的早期睡眠扰动。此外，我们假设该肾小球的增长增强反映了较高的突触添加率。该提案将基于1）确定控制多巴胺能活动发展变化的机制，2）表明，关键时期睡眠剥夺会损害成人行为的正常发育计划，以及3）测试睡眠在突触发生中的作用。拟议的科学调查，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博士能够成功地成为独立的医生 - 科学家。