Development and Function of Sleep Circuits

我们目前对连接大脑的遗传和分子机制知之甚少。 一生中对睡眠的发展和适当的调节。理解这些机制是一种 睡眠生物学的长期挑战，具有很大的临床意义。神经发育障碍包括 自闭症很普遍，并与睡眠障碍密切相关，但潜在的遗传和 神经解剖学机制仍不清楚。我们的研究使用了强大的果蝇模型系统来 描述一条保守的遗传途径，其活性在神经元发育过程中是必需的 成年后的睡眠调节。该途径由失眠症(Inc)、cullin-3(CUL3)泛素组成 连接酶和他们的目标。在发育中的大脑中，这一通路的活性降低严重缩短了持续时间 以及成年后睡眠的巩固。我们的发现表明，这条途径有两个不同的发育阶段 影响苍蝇睡眠调节中枢蘑菇体结构和功能的功能 大脑。在目标1中，我们将确定Inc.是否作用于神经母细胞以控制细胞的增殖和数量 睡眠调节神经元。我们还将验证Inc.基板，包括可能将Inc.链接到的目标 不对称的神经母细胞分裂。在目标2中，我们将确定Inc.是否在有丝分裂后调节 睡眠调节神经元的结构和解剖。在目标3中，我们将确定Inc.如何影响 睡眠调节回路。因为所有研究中的基因都是保守的，并在 哺乳动物的大脑，我们的研究可能为了解正常睡眠、睡眠 功能障碍，以及各种神经紊乱。

We have little current understanding of the genetic and molecular mechanisms that link brain development and the proper regulation of sleep throughout life. Understanding these mechanisms is a longstanding challenge in sleep biology with great clinical relevance. Neurodevelopmental disorders including autism are prevalent and closely associated with sleep disturbances, but the underlying genetic and neuroanatomical mechanisms remain obscure. Our studies use the powerful Drosophila model system to characterize a conserved genetic pathway whose activity is required during neuronal development for the sleep regulation in adulthood. This pathway is composed of Insomniac (Inc), the Cullin-3 (Cul3) ubiquitin ligase, and their targets. Reduced activity of this pathway in the developing brain severely curtails the duration and consolidation of sleep in adulthood. Our findings suggest that this pathway has two distinct developmental functions that influence the structure and function of the mushroom body, a sleep regulatory center in the fly brain. In Aim 1 we will determine whether inc acts in neuroblasts to control the proliferation and number of sleep-regulatory neurons. We will also validate Inc substrates, including a target that may link Inc to asymmetric neuroblast division. In Aim 2, we will determine whether inc acts post-mitotically to regulate the structure and anatomy of sleep-regulatory neurons. In Aim 3, we will determine how inc affects the function of sleep-regulatory circuits. Because all of the genes under study are conserved and expressed in the mammalian brain, our studies may provide insight into mechanisms underlying normal sleep, sleep dysfunction, and various neurological disorders.