Engram encoding for ethanol tolerance in Drosophila

项目总结/摘要 这个建议的目标是捕捉和描述果蝇乙醇耐受性的印迹。 记忆痕迹是神经元及其分子变化，编码持久的行为变化。记忆印痕 描述的哺乳动物中的乙醇仅限于特定的脑区域、编码因子和行为状态， 而对乙醇印迹中的效应子知之甚少。果蝇提供显著更高的吞吐量， 全脑记忆痕迹捕获，多种类型的潜在记忆痕迹的测试，以及 编码机制。此外，我们还开发了快速、慢性和重复暴露的行为模式 我们发现它们是由不同的立即早期基因转录因子编码的。我们 将开发一种新的方法来永久标记大脑中的记忆痕迹。永久性标记让我们定义分子 记忆印迹神经元的变化，探索它们在获得耐受性并随后表达时的功能，并定义 它们在大脑回路中的功能。比较不同形式耐受的解剖学和效应分子将 揭示了乙醇对大脑的复杂作用。我们对进化保守因子的关注提供了一个 为酒精使用障碍的诊断和治疗的未来发展的手段。

Project Summary/Abstract The goal of this proposal is to capture and then characterize engrams for ethanol tolerance in Drosophila. Engrams are the neurons and their molecular changes that encode lasting behavioral change. Engrams described for ethanol in mammals are limited to specific brain regions, encoding factors, and behavioral states, and little is known about effectors in ethanol engrams. Drosophila offer significantly higher throughput, facilitating whole brain capture of engrams, testing of multiple types of potential engrams, and molecular discovery of the mechanisms of encoding. Further, we developed behavioral paradigms for rapid, chronic, and repeated exposure tolerance, and we discovered that they are encoded by distinct immediate early gene transcription factors. We will develop a new method to permanently tag engrams in the brain. Permanent tagging lets us define molecular changes in engram neurons, explore their function as tolerance is acquired and then expressed, and to define their function in brain circuits. Comparing the anatomy and effector molecules for different forms of tolerance will unveil the complex actions of ethanol on the brain. Our focus on evolutionarily conserved factors provides a means for future development of diagnostics and therapeutics for alcohol use disorders.