Sleep Regulation and Function in Early Brain Development

早期大脑发育中的睡眠调节和功能

• 批准号: 10044003
• 负责人: Jaclyn M Durkin
• 金额: $ 6.49万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044003
• 关键词: Adult; Affect; Anatomy; Arousal; Automobile Driving; Behavioral; Biological Models; Brain; Brain region; Cell Count; Cellular Morphology; Coupling; Data; Development; Drosophila genus; Future; Genes; Genetic; Genetic Identity; Genetic Transcription; Goals; Harvest; Homeostasis; Impairment; Insecta; Investigation; Label; Laboratories; Larva; Learning; Life; Lobe; Logic; Mammals; Mediating; Memory; Molecular; Mushroom Bodies; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neuropeptides; Neurotransmitters; Octopamine; Pattern; Play; Population; RNA Interference; Regulation; Research; Role; Short-Term Memory; Sleep; Sleep Deprivation; Sleep disturbances; Structure; Synapses; Synaptic plasticity; System; Techniques; Testing; Time; Training; Visualization; Work; base; comorbidity; experimental study; fly; insight; knock-down; nerve stem cell; nervous system development; neural circuit; neurobehavioral; neuroblast; neurochemistry; neurodevelopment; neurogenesis; neuromechanism; novel; optogenetics; programs; receptor; relating to nervous system; release factor; sensor; sleep regulation; tool; transcriptome sequencing

Sleep during early developmental periods plays a critical role in brain maturation. However, the neural circuits and mechanisms regulating early developmental sleep are not well understood. Furthermore, investigations into the function of sleep during the earliest stages of neural development have been restricted by the lack of a tractable model system. Here, I propose using Drosophila larvae as a platform for dissecting the circuits regulating early developmental sleep. Our lab has performed a neuronal activation screen in restricted populations to determine subsets of neurons that drive sleep in Drosophila larvae. I will characterize sleep- promoting neurons identified in this screen and determine the sleep-promoting factors released by these neurons. I will then assess the connectivity of identified sleep-promoting neurons with known wake-promoting octopamine neurons to gain insight into the logic of sleep:wake regulation during early development. Using immortalization genetics, I will label sleep-promoting neurons to determine their fate and function in the adult brain. Our previous work has demonstrated that early-life sleep deprivation impairs neural proliferation. However, it is unclear how sleep-deprivation during development affects patterning of the adult brain. I will examine the effects of early-life sleep deprivation on the development of the Mushroom Body (MB), a well- characterized insect learning center. I will determine how structure and function of the MB are altered by sleep deprivation, and further assess the effects on a MB-dependent learning paradigm in adult flies. Finally, I will perform RNA-seq to identify novel genes coupling sleep and neural proliferation. Together, the proposed experiments will identify circuits regulating developmentally-timed sleep and provide insight into the function of sleep in the earliest stages of neural development.

早期发育阶段的睡眠对大脑成熟起着至关重要的作用。然而，调节早期发育睡眠的神经回路和机制尚不清楚。此外，由于缺乏可处理的模型系统，对神经发育早期睡眠功能的研究受到了限制。在这里，我建议使用果蝇幼虫作为平台来剖析调节早期发育睡眠的电路。我们的实验室在有限的种群中进行了神经元激活筛选，以确定驱动果蝇幼虫睡眠的神经元子集。我将描述在这个屏幕中发现的促进睡眠的神经元，并确定这些神经元释放的促进睡眠的因素。然后，我将评估已识别的促进睡眠的神经元与已知的促进觉醒的章鱼胺神经元的连通性，以深入了解睡眠的逻辑：早期发育期间的觉醒调节。利用永生遗传学，我将标记促进睡眠的神经元，以确定它们在成人大脑中的命运和功能。我们之前的工作已经证明，早期睡眠剥夺会损害神经细胞的增殖。然而，目前尚不清楚发育过程中的睡眠剥夺如何影响成人大脑的模式。我将检查早期睡眠剥夺对蘑菇体（MB）发育的影响，蘑菇体是昆虫学习中心的一个很好的特征。我将确定睡眠剥夺如何改变脑前部的结构和功能，并进一步评估对成年果蝇脑前部依赖学习范式的影响。最后，我将进行RNA-seq，以确定耦合睡眠和神经增殖的新基因。总之，拟议的实验将确定调节发育时间睡眠的电路，并为神经发育早期阶段睡眠的功能提供见解。