Role of Drosophila circadian circuitry in experience-dependent sleep

描述（由申请人提供）：已证明睡眠在人类、大鼠和苍蝇的记忆巩固中起重要作用（Stickgold等人，2000，Ganguly-Fitzgerald等人，2006）。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 et al，2007，德克尔et al，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重要作用。我们之前已经表明，野生型果蝇在社交丰富的环境中饲养数天后表现出睡眠增加，并且在导致长期记忆形成的求偶条件反射测定中训练后睡眠也增加（Ganguly-Fitzgerald等人，2006）。这种睡眠的增加依赖于典型的学习和记忆基因，如腺苷酸环化酶rutabaga，并且在开灯后的最初几个小时内最大，这表明生物钟的参与。虽然我也发现了两个基因的突变，这两个基因与调节突触可塑性有关，dDA 1多巴胺受体和birthred转录因子。这两种基因都在昼夜节律起搏细胞中内源性表达。因此，拟议中的实验将测试这样一个假设：生物钟回路调节社交丰富后睡眠的增加，而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dDA 1的表达是否参与经验依赖性睡眠的调节。第二，我将研究是否表达果蝇同源哺乳动物血清反应因子，birthred，在昼夜节律起搏细胞参与控制经验依赖性睡眠。最后，我将检验这一假设，即生物钟细胞中突触终末数量的经验依赖性增加需要besterred。研究相关性：睡眠对于巩固人类和果蝇新形成的记忆成为更持久的联系是必要的。考虑到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模型系统来识别在新的社会经历后参与调节睡眠的大脑回路。我假设，以前被确定为昼夜节律振荡器的细胞参与了经验依赖性睡眠的控制。

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.