Investigation of Neuropeptide Signaling Mechanisms that Control Sleep

睡眠障碍越来越常见，并与各种合并症和其他公共疾病有关 对健康的影响。因此，提高我们对控制神经机制的理解是至关重要的 睡眠的时间和质量。调节动物睡眠的关键信号分子，从苍蝇到 人类来自神经肽递质家族。这些分子具有稀疏的表达水平和 对行为的选择性影响，包括睡眠，使它们成为注意力集中发展的主要候选者 副作用最小的药物治疗。然而，这些分子单独作用的机制 并协同调节大脑中的靶细胞，因此人们对其行为知之甚少。此次续订 应用程序将利用强大的遗传学和相对简单的睡眠网络组织 果蝇，黑腹果蝇，解决神经肽如何在分子，细胞和 调节睡眠的行为水平。在目标1中，我们将利用特定神经元亚群的光基因激活 表达睡眠促进递质短神经肽F(SNPF)以确定其特异性 在睡眠调节中的作用。在目标2中，我们将共同激活促进睡眠的sNPF神经元和促进觉醒的神经元 以确定其在睡眠调节中的等级组织。在目标3中，我们将使用实时荧光 成像以检验sNPF对调节亮氨酸神经元的抑制输出信号的假设 睡吧。结合起来，这项拟议的工作将使我们能够确定sNPF神经元在睡眠中如何发挥作用 大脑中的调节网络，扩大了我们对控制睡眠和 分子和电路水平上的觉醒。反过来，这些知识将为设计更多的 有效治疗人类睡眠异常。这份R15地区更新提案将直接涉及 本科生参与研究的方方面面，包括设计和开展涉及 基因操作技术、分子和细胞神经生物学以及行为分析。学生们将 还在传播通过其研究获得的科学知识方面发挥积极作用 会议报告和出版的手稿。他们的经历将为未来的成才提供培训 生物医学领域的职业。

Sleep disturbances are increasingly common and are associated with a variety of comorbidities and other public health consequences. It is therefore critical to improve our understanding of the neural mechanisms that control the timing and quality of sleep. Key signaling molecules that regulate sleep in animals ranging from flies to humans come from the family of neuropeptide transmitters. These molecules have sparse expression levels and selective effects on behavior, including sleep, making them prime candidates for the development of focused drug treatments with minimal side effects. However, the mechanisms by which these molecules act individually and in concert to regulate target cells in the brain and thus behavior are poorly understood. This renewal application will take advantage of the powerful genetics and relatively simple sleep network organization of the fruit fly, Drosophila melanogaster, to address how neuropeptides function at the molecular, cellular, and behavioral levels to regulate sleep. In Aim 1, we will utilize optogenetic activation of specific subsets of neurons expressing the sleep-promoting transmitter short neuropeptide F (sNPF) in order to determine their particular roles in sleep regulation. In Aim 2, we will coactivate sleep-promoting sNPF neurons and wake-promoting neurons to determine their hierarchical organization in sleep regulation. In Aim 3, we will utilize live fluorescent imaging to test the hypothesis that sNPF acts as an inhibitory output signal onto leucokinin neurons that regulate sleep. In combination, the proposed work will allow us to establish how sNPF neurons function within sleep regulatory networks in the brain, expanding our understanding of the mechanisms that control sleep and wakefulness at the molecular and circuit levels. In turn, this knowledge will provide a basis for the design of more effective treatments of human sleep abnormalities. This R15 AREA renewal proposal will directly involve undergraduate students in all aspects of the research, including designing and carrying out studies involving techniques of genetic manipulation, molecular and cellular neurobiology, and behavioral analysis. Students will also take an active role in disseminating the scientific knowledge acquired through their research, in the form of conference presentations and published manuscripts. Their experiences will provide formative training for future careers in biomedical fields.