Molecular and genetic analysis of the juvenile sleep state

项目总结 早年睡眠被认为是为了促进大脑结构的成熟。童年睡眠障碍 预示着较晚的神经认知缺陷，并且在神经行为障碍中非常普遍；睡眠 事实上，发育过程中的异常可能会导致神经回路的异常形成。改善睡眠 因此，靶向调控通路可能代表着神经发育的一条新的治疗途径 疾病。然而，控制早期睡眠的分子和遗传因素在很大程度上仍然未知， 妨碍睡眠相关策略的设计。事实上，目前还没有已知的控制发育的基因 更改为睡眠状态。利用基于RNAi的遗传筛选，我们在果蝇中鉴定了一个转录因子， Pdm3，它调节青少年的睡眠状态。这项提案的总体目标是描述基因的特征 以及通过研究PDM3在青少年睡眠中的作用来控制青少年睡眠状态的分子途径 果蝇。具体来说，我们将定义PDM3控制青少年睡眠的细胞机制 (目标1)并确定PDM3下游协调睡眠个体发生的分子信号(目标2)。我们 然后将操作pdm3来调查青少年睡眠状态的丧失如何影响大脑和行为 成熟(目标3)。我们的建议利用了一系列不同的方法，包括行为、遗传和 成像。剖析睡眠个体发育的分子遗传控制将为睡眠个体发育的调控提供新的见解。 早年睡眠，加深了我们对睡眠个体发育和神经行为之间联系的理解 病理学。

PROJECT SUMMARY Sleep in early life is hypothesized to facilitate structural maturation of the brain. Childhood sleep disturbances portend later neurocognitive deficits and are highly prevalent across neurobehavioral disorders; sleep abnormalities during development may in fact contribute to aberrant neural circuit formation. Improving sleep by targeting regulatory pathways may thus represent a new therapeutic avenue in neurodevelopmental disease. However, the molecular and genetic factors controlling early life sleep remain largely unknown, hindering design of sleep-related strategies. In fact, there have been no genes known to control developmental changes to sleep. Using an RNAi-based genetic screen in Drosophila, we identified a transcription factor, pdm3, that regulates the juvenile sleep state. The overall goal of this proposal is to characterize the genetic and molecular pathways controlling the juvenile sleep state by investigating the function of PDM3 in Drosophila. Specifically, we will define the cellular mechanisms through which PDM3 controls juvenile sleep (Aim 1) and identify the molecular signals downstream of PDM3 that coordinate sleep ontogeny (Aim 2). We will then manipulate pdm3 to investigate how loss of the juvenile sleep state affects brain and behavioral maturation (Aim 3). Our proposal utilizes a diverse array of approaches, including behavioral, genetic, and imaging. Dissecting the molecular genetic control of sleep ontogeny will yield new insights into the regulation of early life sleep, deepening our understanding of the link between sleep ontogeny and neurobehavioral pathology.