Sex-Specific Neuroimmune Molecular Networks Underlying Adolescent Vulnerability to Drugs of Abuse

项目摘要 青少年是一个脆弱的时期，在这一时期，吸毒可能对青少年产生持久的负面影响。 成年然而，这种脆弱性背后的生物学，以及药物如何在治疗过程中改变大脑， 青春期，未知。此外，尚不清楚男性和女性是否同样容易受到药物使用的影响。 在青春期，如果他们的脆弱性是由于相同的分子过程。一种关键的细胞类型， 在这个青春期的关键时期发挥作用的是大脑中的常驻免疫细胞， 小胶质细胞该项目将探索小胶质细胞在受滥用药物严重影响的大脑区域中的作用， 在雄性和雌性大鼠中的丘脑核（NAc）。为此，我将首先描述 小胶质细胞参与的过程在青春期塑造了NAc的发展。建筑 在此基础上，我接下来将评估青少年药物使用如何改变小胶质细胞在这些自然过程中的功能。 最后，我将确定这些观察的行为相关性，通过靶向小胶质细胞依赖 在青少年NAC期间，在药物使用过程中以前确定的过程。因为所有的实验都将 在雄性和雌性大鼠中进行，该项目准备确定是否存在性别依赖性 调节易受药物使用影响的分子过程。我希望这个项目有几个新的 通过桥接三个研究机构的影响，这些机构尚未被认为是不同的：（一）分子 成瘾脆弱性的潜在过程，（ii）对滥用药物的神经免疫反应，以及（iii） 长期禁欲后复发的生物学。

PROJECT SUMMARY Adolescence is a vulnerable time period in which drug use can have lasting negative consequences into adulthood. However, the biology underlying this vulnerability, and how drugs modify the brain during adolescence, is unknown. Furthermore, it is unclear if males and females are equally vulnerable to drug use during adolescence, and if their vulnerability is due to the same molecular processes. One critical cell type that has been implicated in playing a role in this adolescent critical period is the resident immune cells of the brain, microglia. This project will explore the role of microglia in a brain region critically influenced by drugs of abuse, the nucleus accumbens (NAc), in male and female rats. To that end, I will first characterize what molecular processes to which microglia contribute that shape the development of the NAc during adolescence. Building upon this, I will next assess how adolescent drug use modifies function of microglia in these natural processes. Finally, I will determine the behavioral relevance of these observations by targeting microglia-dependent processes previously identified during adolescent NAc during drug use. Moreover, because all experiments will be performed in both male and female rats, this project is poised to determine if there is a sex-dependent regulation of molecular processes vulnerable to drug use. I expect this project to have several novel implications by bridging three bodies of research that are as yet considered disparate: (i) the molecular processes underlying vulnerability to addiction, (ii) neuroimmune responses to drugs of abuse, and (iii) the biology of relapse after long periods of abstinence.