Investigating the role of dSERT activity in Drosophila Sleep

摘要： 睡眠是生命中必不可少的关键过程，在许多物种中都是保守的。虽然 睡眠中断与各种神经和精神疾病有关，细胞 涉及睡眠调节的机制和神经回路还没有被很好地理解。生源 胺5-羟色胺（5-hydroxytryptamine，5-HT）是睡眠行为的重要神经调节剂 从昆虫到哺乳动物。肾上腺素能信号和睡眠之间的关系一直是 研究了几十年，但它在睡眠调节中的复杂作用仍然不确定， 许多研究表明它在觉醒和相反的睡眠倾向中起作用。这些 许多抗抑郁药和抗焦虑药 通过选择性抑制5-羟色胺再摄取（SSRIs）发挥作用的药物已被证明， 对睡眠产生矛盾和各种影响，从失眠到白天嗜睡。在 果蝇和哺乳动物从突触间隙重摄取5-羟色胺都是通过 血清素转运蛋白（SERT）。睡眠、神经系统疾病和SSRI之间的关系 药物治疗强烈表明，细胞外5-羟色胺水平的变化，由于增加 或SERT活性降低可能在调节睡眠行为中起关键作用。分子 然而，这一过程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，我建议使用果蝇作为模型系统来研究 改变果蝇SERT（dSERT）活性可能影响睡眠行为的机制。我会 首先生成最前沿的遗传工具来探测dSERT的功能，然后将其实现 这些工具来询问睡眠行为。我的训练将在克兰茨和唐利进行 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。为了实现 为了实现这些目标，我将接受神经科学专家的培训，并与当地专家合作。另外我 我将充分利用加州大学洛杉矶分校提供的课程、研讨会、期刊俱乐部和讲习班的丰富资源 外部来源。这些实验将阐明细胞外5-羟色胺信号传导在 睡眠生理学，并确定参与这种行为的多巴胺能电路。这项工作 研究睡眠环境中神经调节的分子机制， 我们对多巴胺能信号如何参与睡眠行为的理解。

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.