Role of Drosophila circadian circuitry in experience-dependent sleep

描述(由申请人提供)：睡眠已被证明在人类、大鼠和苍蝇的记忆巩固中发挥重要作用(StickGold等人，2000年，Ganguly-Fitzgerald等人，2006年)。最近的研究表明，除了在睡眠调节中发挥重要作用外，生物钟还影响与学习和记忆相关的过程(Keisler等人，2007，Decker等人，2007)。因此，控制昼夜节律的神经元回路在协调睡眠和记忆之间的相互作用方面发挥着独特的作用。我们之前已经证明，野生型果蝇在社交丰富的环境中生活了几天后表现出更多的睡眠，并且在导致长期记忆形成的求偶条件反射测试中进行训练后，睡眠也会增加(Gangly-Fitzgerald等人，2006年)。睡眠的增加依赖于典型的学习和记忆基因，如腺苷环化酶rutabaga，并且在点灯后的最初几个小时最大，这表明生物钟参与了睡眠。虽然我也发现了参与调节突触可塑性的两个基因的突变，dDA1多巴胺受体和水泡转录因子。这两个基因都在昼夜节律起搏细胞中内源性表达。因此，拟议中的实验将检验这样一种假设，即生物钟电路调节社交丰富后增加的睡眠，并且这种调节需要已知参与记忆形成的基因的表达。首先，我将测试昼夜节律回路中多巴胺受体dDA1的表达是否参与经验依赖型睡眠的调节。其次，我将研究果蝇与哺乳动物血清反应因子水泡同源基因在昼夜节律起搏细胞中的表达是否与控制经验依赖型睡眠有关。最后，我将验证这一假设，即昼夜节律时钟细胞中突触终末数量的经验依赖性增加需要水泡。研究意义：在人类和果蝇中，睡眠对于巩固新形成的记忆到更持久的联想中是必要的。鉴于人类和果蝇睡眠之间的相似性，以及可用于研究果蝇的遗传工具，我建议使用果蝇作为一个模型系统，以确定在新奇的社会经历后参与调节睡眠的大脑回路。我推测，以前被确认为昼夜节律振荡器的细胞参与了经验依赖型睡眠的控制。

DESCRIPTION (provided by applicant): Sleep has been shown to play an important role in the consolidation of memories in humans, rats and flies (Stickgold et-al, 2000, Ganguly-Fitzgerald et al, 2006). Recent studies have shown that, in addition to playing a strong role in sleep regulation, the circadian clock also influences processes associatedwith learning and;memory (Keisler et al, 2007, Decker et al, 2007). Thus, the neuronal circuits that control circadian rhythms are uniquely positioned to play an important role in coordinating interactions between sleep and memory. We have previously shown that wild-type Drosophila exhibit increased sleep after being housed for several days in a socially-enriched environment and that sleep is also increased following training in a courtship conditioning assay that results in the formation of long-term memories (Ganguly- Fitzgerald et al, 2006). This increase in sleep is dependent on canonical learning and memory genes such as the adenylyl cyclase rutabaga and is largest during the initial hours after lights-on suggesting the involvement of the circadian clock. Although I have also found that mutations in two genes that are involved in regulating synaptic plasticity, the dDA1 dopamine receptor and the blistered transcription factor. Both of these genes are endogenously expressed in circadian pacemaker cells. Thus, the proposed experiments will test the hypothesis that circadian clock circuits regulate increased sleep following social enrichment and that this regulation requires the expression of genes known to be involved in memory formation. First, I will test whether expression of the dopamine receptor dDA1 in circadian circuitry is involved in regulation of experience-dependent sleep. Second, I will examine whether expression of the Drosophila homolog to the mammalian Serum Response Factor, blistered, in circadian pacemaker cells is involved in controlling experience-dependent sleep. Finally, I will test the hypothesis that blistered is required for experience- dependent increase of synaptic terminal number in circadian clock cells. Research Relevance: Sleep is necessary for consolidation of newly formed memories into longer lasting associations in humans and in fruit flies. Given the similarities between sleep in humans and in flies and the genetic tools that are available to study the fruit fly, I propose to use the fruit fly as a model system to identify a brain circuit that is involved in regulating sleep after novel social experiences. I hypothesize that cells that have been previously identified as circadian oscillators are involved in the control of experience-dependent sleep.