The influence of peroxisome proliferator-activated receptor gamma coactivator - 1 alpha (PGC-1a) on the nucleus accumbens during cocaine-self-administration

项目总结/摘要 吸毒成瘾给社会造成巨大的经济和人力代价。吸毒成瘾往往是 其特点是持续的药物寻求和复发的脆弱性，这是成瘾的巨大障碍 治疗即使在长期禁欲后也可能发生复发，并且通常在强烈的药物渴望之前 通过暴露于药物配对刺激和环境而沉淀。这种对药物渴望的心理坚持 寻求与滥用药物引起的自然奖赏相关系统的神经生物学变化有关。然而，在这方面， 药物消耗后发生神经可塑性的细胞类型特异性分子机制， 不完全理解。越来越多的研究表明，线粒体的健康和调节对于 与物质使用障碍和精神疾病相关的神经元修饰。在这里，我的目标是确定 可卡因如何改变D1-中等多棘神经元（D1-MSNs）内的转录调控，通过 转录辅激活因子过氧化物酶体增殖物激活受体γ辅激活因子1-α（PGC- 1α）。先前的工作和初步数据表明，可卡因增加PGC-1α的表达，特别是在D1- MSNs，增加D1-MSN棘密度，并通过增加小线粒体的数量增加 线粒体分裂此外，外源性增加PGC-1α会夸大可卡因相关行为，如 运动敏感化和条件性位置偏爱。尽管有这些发现，PGC- 1α以及可卡因后在D1-MSNs中观察到的棘和线粒体变化尚未得到证实， PGC-1α在可卡因寻求行为表达中的必要性也没有得到证实。我假设 可卡因改变药物寻求行为，MSN棘密度和线粒体形态，通过增加 PGC-1α的表达和功能，减少D1-MSN中PGC-1α的表达将阻断这一点。 可卡因诱发的可塑性本提案目标1的实验将检验这一假设。此外，在目标2中， 我将使用染色质确定可卡因自我给药后PGC-1α与哪些基因相互作用 免疫沉淀。然后，我将专门测量PGC-1α靶向基因的表达， 可卡因自我给药后D1-MSNs的线粒体和脊柱可塑性。共同利用尖端技术 行为和分子技术，这些实验将确定PGC-1α在可卡因中的重要性， 诱导分子和细胞的变化，介导可卡因SA和寻求。这些目标综合了我的 对行为分子调节剂的兴趣，我的赞助人在解剖细胞类型选择基因方面的专长 纹状体的表达，以及马里兰州大学神经科学学院不同教师的经验， 药物，以提高我们对介导药物渴求的神经机制的理解。这项工作将既 提高我们预测复发脆弱性和确定有效药物治疗的潜力，并将 提供一个强大的平台，开始我的独立科学生涯

Project Summary/Abstract Addiction to drugs of abuse exacts massive economic and human costs upon society. Drug addiction is often characterized by persistant drug seeking and vulnerability to relapse, which are huge barriers to addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. This psychological persistence in drug craving and seeking is tied to neurobiological changes of natural reward related systems by drugs of abuse. However, the cell type-specific molecular mechanisms by which neuroplasticity takes place following drug consumption is incompletely understood. A growing body of work indicates mitochondrial health and regulation are important for neuronal modifications associated with substance use disorders and psychiatric illness. Here, I aim to identify how cocaine alters transcriptional regulation within D1- medium spiny neurons (D1-MSNs) via the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC- 1α). Previous work and preliminary data show that cocaine increases PGC-1α expression specifically in D1- MSNs, increases D1-MSN spine density, and increases the number of small mitochondria via increased mitochondrial fission. Further, exogenously increasing PGC-1α exaggerates cocaine-related behaviors like locomotor sensitization and conditioned place preference. Despite these findings, a causal link between PGC- 1α and the spine and mitochondrial changes observed in D1-MSNs after cocaine has not been demonstrated, nor has the necessity of PGC-1α for the expression of cocaine seeking behavior been established. I hypothesize that cocaine alters drug seeking behavior, MSN spine density, and mitochondrial morphology by increasing the expression and function of PGC-1α, and that reducing the expression of PGC-1α in D1-MSNs will block this cocaine-induced plasticity. The experiments of Aim 1 of this proposal will test this hypothesis. Further, in Aim 2, I will determine what genes PGC-1α interacts with after cocaine self-administration using chromatin immunoprecipitation. I will then specifically measure the expression of PGC-1α-targeted genes that are involved in mitochondrial and spine plasticity in D1-MSNs after cocaine self-administration. Together, using cutting edge behavioral and molecular techniques, these experiments will establish the importance of PGC-1α in cocaine- induced molecular and cellular changes that mediate cocaine SA and seeking. These aims synthesize my interest in molecular mediators of behavior, my sponsor’s expertise in dissecting cell-type selective gene expression in the striatum, and the experience of the diverse faculty at the University of Maryland School of Medicine to improve our understanding of the neuronal mechanisms mediating drug craving. This work will both improve our potential to predict relapse vulnerability and identify effective pharmacological therapies, and will provide a strong platform to launch my independent career in science