Gene Regulation in Memory Circuits as a Consequence of Polysubstance Use

项目总结： 甲基苯丙胺是一种高度上瘾的毒品，对大脑的学习和记忆有重大影响 系统。甲基苯丙胺的使用通常是通过大量使用合法的精神刺激剂来预测的，如尼古丁或 酒精，但酒精、尼古丁和甲基苯丙胺的连续使用背后的机制并不好 明白了。尼古丁和酒精都会改变适应性决策所需的大脑回路的功能，但 这种情况发生的细胞和分子机制在很大程度上仍然是一个谜。鉴定基因 在高酒精或高尼古丁的特定回路内的调控网络寻找动物并破译 甲基苯丙胺改变这些网络是破译基本分子基础所必需的 通过甲基苯丙胺影响不适应的选择。然而，电路和单元的多样性 参与这些反应已经混淆了我们识别关键分子途径的能力。我们的目标是使用 基因-回路-行为方法在果蝇中提供创新和整体 理解连续使用精神刺激剂改变心理刺激的核心基本原则 改变行为决定的记忆回路的分子景观和神经动力学。转录的 记忆回路内的调节是心理刺激驱动适应不良的基本过程 大脑功能的变化。这项工作提供了致病基因调控机制，通过这些机制 对酒精或尼古丁的偏好会影响记忆回路中的甲基苯丙胺反应。这个有很大的 联合使用精神刺激剂如何改变驱动药物寻找的分子格局 行为。

PROJECT SUMMARY: Methamphetamine is a highly addictive drug that has major effects on the brain’s learning and memory systems. Methamphetamine use is commonly predicted by high use of legal psychostimulants such nicotine or alcohol, but the mechanisms underlying sequential use of alcohol, nicotine and methamphetamine are not well understood. Both nicotine and alcohol alter the function of brain circuits required for adaptive decisions, but the cellular and molecular mechanisms through which this occurs largely remain a mystery. Identifying the gene regulatory networks within select circuits in high alcohol or high nicotine seeking animals and deciphering how methamphetamine alters these networks is necessary to decode the fundamental molecular underpinnings through which methamphetamine influences maladaptive choice. However, the diversity of circuits and cells involved in these responses has confounded our ability to identify key molecular pathways. Our goal is to use a genes-circuits-behavior approach in Drosophila melanogaster to provide an innovative and holistic understanding of the core fundamental principles through which sequential use of psychostimulants alter the molecular landscape and neural dynamics of memory circuits to alter behavioral decisions. Transcriptional regulation within memory circuits is a fundamental process through which psychostimulants drive maladaptive changes in the brain function. This work provides the causal gene regulatory mechanisms through which high preference for alcohol or nicotine affects methamphetamine response in memory circuits. This has major implications for how co-use of psychostimulants alters the molecular landscape that drives drug-seeking behavior.