The Function of Sleep in Critical Period Plasticity

项目摘要 尽管我们一生中有三分之一的时间在睡觉，但这种进化上保守的行为的功能 仍然难以捉摸。大多数研究睡眠功能的研究都集中在成年人的睡眠上。 然而，幼年动物一生中更大比例的时间是在睡眠中度过的，它们的睡眠 较深，具有明显的电生理特征。幼年动物的睡眠被认为有助于大脑 通过促进可塑性来发展。这些塑化过程发生在关键时期， 神经回路是由经验塑造的。然而，分子、细胞和电路机制通过 哪些睡眠功能在关键期可塑性仍然难以捉摸。本提案旨在解决这一问题。 通过在遗传易驯化的模型生物体中使用简单的神经电路来提出问题。在《目标1》中，我将 使用行为特征和统计建模以及成像来定义睡眠子阶段 方法，然后确定关键期可塑性是否需要特定形式的睡眠。在目标2中，我 将研究睡眠促进关键期可塑性的神经生理过程 使用膜片钳电生理学并研究在这一过程中重要的基因 使用单细胞RNA测序。在Aim 3中，我将使用 行为分析，寻找与睡眠依赖关键期可塑性有关的新基因。在……里面 此外，我将调查睡眠相关的神经活动是否由星形胶质细胞产生以帮助 临界时期塑性。总体而言，这些目标将描绘出年轻人特定睡眠状态的功能 并确定睡眠依赖关键期的细胞和分子机制 可塑性。因为早年的睡眠障碍是神经认知障碍的预测指标，如 自闭症和注意力缺陷障碍，这项工作可能对治疗 神经发育状况。为了实现这些目标，我组建了一个指导团队 其中包括计算建模、转录图谱和发育神经方面的专家 可塑性。此外，拟议的职业发展和研究计划将利用 约翰霍普金斯大学提供的特殊环境、设施和资源。我的 主要的职业目标是获得终身教职，跟踪教师的职位，并建立自己的研究 作为一名独立的科学家，计划和建议的工作和培训将形成强大的 为实现这一目标奠定基础。

Project Summary Although we spend a third of our lives sleeping, the function of this evolutionarily conserved behavior remains elusive. Most studies investigating the function of sleep have focused on sleep in adults. However, young animals spend an even greater proportion of their lives asleep, and their sleep is deeper and has distinct electrophysiological features. Sleep in young animals is thought to aid brain development by promoting plasticity. These plastic processes occur during critical periods in which neural circuits are shaped by experience. Yet, the molecular, cellular and circuit mechanisms by which sleep functions in critical period plasticity remains elusive. This proposal aims to address this question by using a simple neural circuit in a genetically tractable model organism. In Aim 1, I will define sleep substages using behavioral features and statistical modeling, as well as imaging methods, and then determine if critical period plasticity requires a specific form of sleep. In Aim 2, I will investigate the neurophysiological processes by which sleep promotes critical period plasticity using patch clamp electrophysiology and investigate the genes that are important for this process using single cell RNA sequencing. In Aim 3, I will perform a large-scale RNAi screen using a behavioral assay to find novel genes that are involved in sleep-dependent critical period plasticity. In addition, I will investigate whether sleep-related neural activity is generated by astrocytes to aid critical period plasticity. Overall, these aims will delineate the function of specific sleep states in young animals and identify cellular and molecular mechanisms underlying sleep-dependent critical period plasticity. Because sleep disturbances in early life are predictors of neurocognitive disorders such as autism and attention deficit disorders, this work may have implications for the treatment of neurodevelopmental conditions. To achieve these aims, I have brought together a mentoring team which includes experts in computational modeling, transcriptional profiling, and developmental neural plasticity. In addition, the proposed career development and research plan will capitalize on the exceptional environment, facilities, and resources that Johns Hopkins University provides. My overarching career goal is to obtain a tenure track faculty position and establish my own research program as an independent scientist, and the proposed work and training will form a strong foundation for achieving this goal.