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

项目总结 青春期是一个脆弱的时期，在这段时间里，吸毒可能会产生持久的负面后果 成人期。然而，这种脆弱性背后的生物学基础，以及药物在治疗过程中如何修改大脑 青春期，是未知的。此外，尚不清楚男性和女性是否同样容易吸毒。 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 在这个青春期关键时期发挥作用的是大脑的常驻免疫细胞， 小胶质细胞。这个项目将探索小胶质细胞在受药物滥用严重影响的大脑区域中的作用， 伏隔核(NAC)，雄性和雌性大鼠。为此，我将首先描述什么分子 小胶质细胞参与的过程塑造了青春期NAC的发育。建房 在此基础上，我接下来将评估青少年药物使用如何在这些自然过程中改变小胶质细胞的功能。 最后，我将通过以依赖小胶质细胞为目标来确定这些观察结果的行为相关性 以前在青少年吸食毒品的NAC期间确定的过程。此外，因为所有的实验都将 在雄性和雌性大鼠身上都进行了实验，该项目准备确定是否存在性别依赖 对易受药物使用影响的分子过程的调控。我希望这个项目有几部小说 通过将迄今被认为不同的三个研究机构联系起来而产生的影响：(I)分子 对成瘾易感性的潜在过程，(2)对滥用药物的神经免疫反应，以及(3) 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.