Gene Regulation in Memory Circuits as a Consequence of Polysubstance Use

多物质使用导致的记忆电路基因调控

• 批准号: 10739399
• 负责人: Karla R. Kaun
• 金额: $ 51.29万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739399
• 关键词: Affect; Alcohol consumption; Alcohols; Animals; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; CREB1 gene; Cells; Chromatin; Coupled; Cues; Drosophila genus; Drosophila melanogaster; Ethanol; Functional Imaging; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Investigation; Learning; Legal; Memory; Methamphetamine; Molecular; Mushroom Bodies; Neuronal Plasticity; Neurons; Nicotine; Odors; Pathway interactions; Pharmaceutical Preparations; Process; Psychological reinforcement; RNA; Regulator Genes; Role; Self Administration; Signal Pathway; System; Testing; Transcriptional Regulation; Volatilization; Work; Youth; alcohol consequences; approach behavior; causal variant; cocaine use; drug of abuse; drug seeking behavior; experimental study; fly; gene discovery; gene regulatory network; individual variation; innovation; methamphetamine exposure; methamphetamine use; neural; neurogenetics; nicotine seeking behavior; nicotine self-administration; nicotine use; opioid use; polysubstance use; preference; psychostimulant; response; stimulant use; synaptic function; tool

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.

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法律的精神兴奋剂如尼古丁或 酒精，但酒精，尼古丁和甲基苯丙胺顺序使用的机制并不清楚 明白尼古丁和酒精都会改变大脑回路的功能，而大脑回路是做出适应性决定所必需的。 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。识别基因 在高酒精或高尼古丁寻求动物的选择电路内的调节网络， 甲基苯丙胺改变这些网络是解码基本分子基础所必需的 甲基苯丙胺影响适应不良的选择然而，电路和细胞的多样性 参与这些反应的分子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-电路-行为的方法，为果蝇提供一个创新的和全面的 理解连续使用精神兴奋剂改变精神状态的核心基本原则。 分子景观和记忆回路的神经动力学来改变行为决定。转录 记忆回路中的调节是一个基本过程，通过这个过程，精神兴奋剂驱动适应不良 大脑功能的变化。这项工作提供了致病基因的调控机制，通过这种机制， 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。这是主要的 共同使用精神兴奋剂如何改变驱动药物寻求的分子景观的影响 行为