Investigating the role of dSERT activity in Drosophila Sleep

研究 dSERT 活性在果蝇睡眠中的作用

• 批准号: 10463579
• 负责人: Elizabeth Knapp
• 金额: $ 6.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463579
• 关键词: Address; Affect; Alleles; Animals; Antidepressive Agents; Behavior; Behavioral; Biogenic Amines; Biological Models; Biology; CRISPR/Cas technology; Cells; Complex; Data; Defect; Down-Regulation; Drosophila genus; Drowsiness; Educational workshop; Exhibits; Future; Gene Expression Profile; Genetic; Human; Insecta; Journals; Laboratories; Life; Link; Mammals; Maps; Mediating; Mental disorders; Modeling; Molecular; Mutation; Neurologic; Neuromodulator; Neurosciences; Neurosciences Research; Pharmaceutical Preparations; Phenotype; Play; Process; Publishing; Resources; Rest; Role; Serotonin; Signal Transduction; Sleep; Sleep disturbances; Sleeplessness; Source; Specialist; Synaptic Cleft; Training; Transgenes; Up-Regulation; Variant; Wakefulness; Work; experimental study; extracellular; fly; in vivo; insight; loss of function; mutant; nervous system disorder; neural circuit; neuroregulation; novel; receptor; reuptake; serotonin receptor; serotonin transporter; sleep behavior; sleep physiology; sleep regulation; tool

Abstract: Sleep is a critical process essential for life and is conserved across many species. Although sleep disruption has been linked to a variety of neurological and psychiatric disorders, the cellular mechanisms and neural circuitry involved in sleep regulation are not well understood. The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) functions as a key neuromodulator of sleep behavior from insects to mammals. The relationship between serotonergic signaling and sleep has been studied for several decades, however its complex role in sleep regulation remains uncertain, with many studies showing it to play a role in both wakefulness and conversely sleep propensity. These complexities are further compounded by the fact that many antidepressants and antianxiety medications that work through selective inhibition of serotonin reuptake (SSRIs) have been shown to produce contradicting and various effects on sleep, ranging from insomnia to daytime somnolence. In both Drosophila and mammals reuptake of serotonin from the synaptic cleft is mediated via the Serotonin Transporter (SERT). The relationships between sleep, neurological disorders, and SSRI medications strongly suggest that variations in extracellular serotonin levels as a result of increased or decreased SERT activity could play a key role in modulating sleep behaviors. The molecular mechanisms underlying this process, however, are not well understood in either humans or model systems. To address these questions, I propose to use Drosophila as a model system to study the mechanisms by which altering Drosophila SERT (dSERT) activity may impact sleep behavior. I will first generate cutting edge genetic tools to probe the function of dSERT, and then I will implement these tools to interrogate sleep behavior. My training will take place in the Krantz and Donlea Laboratories at UCLA, a world-renowned center for neuroscience research. In order to accomplish these aims, I will train under neuroscience experts and collaborate with local specialists. In addition, I will utilize the ample resources of classes, seminars, journal clubs and workshops offered by UCLA and external sources. These experiments will elucidate the role of extracellular serotonin signaling in sleep physiology and identify the serotonergic circuitry involved in this behavior. This work investigates the molecular mechanisms of neuromodulation in the context of sleep and will enhance our understanding of how serotonergic signaling is involved in sleep behavior.

摘要： 睡眠是生命必不可少的一个关键过程，在许多物种中都是保守的。虽然 睡眠障碍与各种神经和精神障碍有关，细胞 参与睡眠调节的机制和神经回路还不是很清楚。生物源 胺5-羟色胺(5-羟色胺，5-羟色胺)是睡眠行为的关键神经调节剂 从昆虫到哺乳动物。5-羟色胺能信号与睡眠之间的关系一直是 然而，经过几十年的研究，它在睡眠调节中的复杂作用仍然不确定， 许多研究表明，它对清醒和睡眠倾向都起到了作用。这些 更复杂的是，许多抗抑郁药物和抗焦虑药物 通过选择性抑制5-羟色胺再摄取(SSRIs)起作用的药物已被证明 对睡眠产生相互矛盾的各种影响，从失眠到白天嗜睡。在……里面 果蝇和哺乳动物从突触间隙重新摄取5-羟色胺是通过 5-羟色胺转运体(SERT)睡眠、神经紊乱和SSRI之间的关系 药物强烈表明，细胞外5-羟色胺水平的变化是由于 或者，SERT活性降低可能在调节睡眠行为方面发挥关键作用。分子 然而，这一过程背后的机制在人类或模型中都没有得到很好的理解。 系统。为了解决这些问题，我建议以果蝇为模型系统来研究 改变果蝇SERT(DSERT)活性可能影响睡眠行为的机制。这就做 首先生成尖端的基因工具来探索dSERT的功能，然后我将实现 这些工具用来审问睡眠行为。我的训练将在《将军》和多尼亚进行 加州大学洛杉矶分校的实验室，世界著名的神经科学研究中心。为了完成 为了实现这些目标，我将在神经科学专家的指导下进行培训，并与当地专家合作。此外，我 将利用加州大学洛杉矶分校提供的课程、研讨会、期刊俱乐部和研讨会等丰富的资源 和外部来源。这些实验将阐明细胞外5-羟色胺信号在 睡眠生理学，并确定参与这一行为的5-羟色胺能回路。这部作品 研究睡眠背景下神经调节的分子机制，并将增强 我们对5-羟色胺能信号如何参与睡眠行为的理解。