Gene Regulation in Memory Circuits as a Consequence of Polysubstance Use

项目概要： 甲基苯丙胺是一种高度成瘾的药物，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兴奋剂（例如尼古丁或尼古丁）来预测的。 酒精，但连续使用酒精、尼古丁和甲基苯丙胺的机制尚不明确 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，但是 这种现象发生的细胞和分子机制在很大程度上仍然是个谜。识别基因 寻找高酒精或高尼古丁动物的特定回路内的监管网络并破译如何 甲基苯丙胺改变这些网络对于解码基本分子基础是必要的 甲基苯丙胺通过它影响适应不良的选择。然而，电路和单元的多样性 参与这些反应的因素混淆了我们识别关键分子途径的能力。我们的目标是使用一个 果蝇的基因-电路-行为方法提供创新和整体的 了解连续使用精神兴奋剂改变精神状态的核心基本原则 记忆回路的分子景观和神经动力学改变行为决策。转录的 记忆回路内的调节是精神兴奋剂驱动适应不良的基本过程 大脑功能的变化。这项工作提供了因果基因调控机制，通过该机制，高 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。这有重大 精神兴奋剂的共同使用如何改变驱动药物寻求的分子景观的影响 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.