Regulation of Learning and Memory by Immediate Early Genes in Drosophila brain

果蝇大脑中早期基因对学习和记忆的调节

• 批准号: 8699046
• 负责人: CRYSTAL Gayle PONTRELLO
• 金额: $ 5.51万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699046
• 关键词: Affect; Alleles; Amylases; Antibodies; Behavior; Behavioral; Behavioral Paradigm; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell physiology; Development; Distal; Drosophila genus; Drosophila melanogaster; Exposure to; FOS gene; Gene Expression; Genes; Genetic; Goals; Heat shock proteins; Homologous Gene; Human; Immediate-Early Genes; Intracellular Signaling Proteins; JUN gene; Lead; Learning; Link; Long-Term Depression; Long-Term Potentiation; Mammals; Maps; Memory; Memory Loss; Methods; Modeling; Molecular; Neurons; Outcome; Process; Proteins; RNA Interference; RNA Probes; Reagent; Regulation; Research; Resolution; Retrieval; Role; Sensory; Specific qualifier value; Stimulus; Synapses; Techniques; Testing; Training; Validation; behavior test; classical conditioning; fly; gene function; genome-wide analysis; insight; knock-down; loss of function; member; memory retrieval; mutant; nervous system disorder; novel; public health relevance; research study; response; screening; therapeutic target; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): While several cellular mechanisms that underlie learning and memory have been well-studied, little is known about the genetic components that contribute to proper memory formation, retention, and retrieval. A special class of genes called immediate early genes (IEGs) is rapidly expressed in neurons in response to activity, and has been implicated in learning and memory. We have initiated a genome-wide analysis of Drosophila melanogaster brains in order to discover novel IEGs that may underlie memory. Our preliminary results have revealed 278 candidate IEGs that are expressed differently in the Drosophila brain after exposure to sensory stimulation, and we have used a high-throughput behavior screen to implicate 28 of these genes so far in learning and memory. In addition to the classical IEGs that are rapidly up-regulated in response to neuronal activity, we have also identified 87 genes that are down-regulated immediately following stimulation, several of which we have implicated in memory using our behavior screen. The goal of this proposal is to delineate the molecular mechanisms by which 6 novel IEGs that we identified, that are conserved in humans, are necessary for learning and memory. We have selected 3 up-regulated genes (CG11964, sallimus, and Amylase distal) and 3 down-regulated genes (Heat-shock-protein-70Ab, Heat-shock-protein- 70Ba, and maggie) that have a variety of molecular functions, which should provide an understanding of the diverse molecular and cellular mechanisms necessary for memory formation and retrieval. We will validate that our IEGs are critical for learning using standard Drosophila tools and techniques such as alternative allele lines and deficiency stocks, and we will map expression of the genes in the brain using RNA probes and antibodies to delineate specific regions that are needed for several different types of learning. We will also investigate a potential developmental role for the genes by knocking down gene expression with RNAi following development. The outcome of our studies will specify the methods by which these 6 specific novel genes are critical for proper memory function. Our results will also provide a greater understanding of normal learning and memory mechanisms, as well as potential therapeutic targets for neurological diseases that result in memory loss.

描述（由申请人提供）：虽然已经对学习和记忆背后的几种细胞机制进行了深入研究，但对于有助于正确记忆形成、保留和检索的遗传成分却知之甚少。一类特殊的基因称为立即早期基因（IEG），在神经元中快速表达以响应活动，并且与学习和记忆有关。我们已经启动了对果蝇大脑的全基因组分析，以发现可能是记忆基础的新型 IEG。我们的初步结果揭示了 278 个候选 IEG，它们在受到感觉刺激后在果蝇大脑中表达不同，并且迄今为止我们已经使用高通量行为筛选将其中 28 个基因与学习和记忆相关。除了响应神经元活动而迅速上调的经典 IEG 之外，我们还发现了 87 个在刺激后立即下调的基因，其中一些基因我们通过行为筛选发现与记忆有关。该提案的目标是描述我们发现的 6 种新的 IEG 的分子机制，这些 IEG 在人类中是保守的，对于学习和记忆是必需的。我们选择了 3 个上调基因（CG11964、sallimus 和 Amylase远端）和 3 个下调基因（Heat-shock- Protein-70Ab、Heat-shock- Protein-70Ba 和 maggie），它们具有多种分子功能，这应该有助于了解记忆形成和检索所需的多种分子和细胞机制。我们将使用标准果蝇工具和技术（例如替代等位基因系和缺陷库）验证我们的 IEG 对于学习至关重要，并且我们将使用 RNA 探针和抗体绘制大脑中基因的表达图谱，以描绘几种不同类型学习所需的特定区域。我们还将通过在发育后用 RNAi 敲低基因表达来研究基因的潜在发育作用。我们的研究结果将具体说明这 6 个特定的新基因对于正常记忆功能至关重要的方法。我们的研究结果还将让人们更好地了解正常的学习和记忆机制，以及导致记忆丧失的神经系统疾病的潜在治疗靶点。