Neural mechanisms of sex differences in vulnerability to the effects of adolescent methamphetamine exposure

青少年易受甲基苯丙胺暴露影响的性别差异的神经机制

基本信息

批准号：
10527234
负责人：
Joshua M Gulley
金额：
$ 21.9万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527234
关键词：
Address Adolescence Adolescent Adolescent Development Adult Affect Aftercare Age Animal Model Animal Testing Animals Behavior Brain CSPG3 gene Chondroitin Sulfate Proteoglycan Data Development Down-Regulation Drug Exposure Drug abuse Drug usage Drug user Exhibits Exposure to Extracellular Matrix Female Female Adolescents Goals Human Individual Intake Interneurons Laboratory Animal Models Lead Life Link Long-Term Effects Medial Messenger RNA Methamphetamine Modeling Motivation Neurons Parvalbumins Pattern Pharmaceutical Preparations Phase Predisposition Prefrontal Cortex Process Proteoglycan Puberty Rattus Relapse Rodent Role Self Administration Sex Differences Structure Substance Use Disorder Testing Time Training Virus addiction aggrecan brevican drug of abuse drug seeking behavior early adolescence experience experimental study gender difference high risk male methamphetamine effect methamphetamine exposure methamphetamine use neural circuit neuromechanism relating to nervous system sex small hairpin RNA stimulant use substance use treatment strategy versican vulnerable adolescent young adult

项目摘要

Project Summary Adolescence is a time of extensive neural reorganization, especially in the prefrontal cortex of both humans and rodents. One of the major changes that occurs in the medial prefrontal cortex is an increase in perineuronal nets (PNNs), an extracellular matrix that preferentially surrounds parvalbumin (PV)-expressing inhibitory interneurons, adding stability and functional support. Our recent data showed that female rats have a decrease in PNNs at puberty, which males do not, and this may result in greater female vulnerability to drug exposure during adolescence and at puberty. The premise of the current proposal is that the process of neural maturation of fast-spiking, inhibitory PV interneurons, and the formation of PNNs and their components in the medial prefrontal cortex, is an essential part of the vulnerability to substance use disorder during adolescence. This will be tested with exposure to a highly abused drug, methamphetamine (METH). Aim 1 will determine the short-term effects of METH exposure on both number and intensity of PV neurons and PNNs when administered at three separate time points: early-adolescence (overlapping with female puberty), late- adolescence (male puberty), or young adulthood. PV neurons, PNNs and their chondroitin sulfate proteoglycan components will be quantified immediately with the pubertal status noted. We hypothesize that there will be decreases in both PV intensity, the number of PNNs and their components, in the medial prefrontal of the adolescent-exposed, compared to an increase in the young adult-exposed. This effect would be indicative of the increased plasticity and resulting vulnerability to METH exposure in adolescence. We predict females in the young adolescent, pubertal group will be the most affected. Aim 2 will test animals that have been exposed to METH in Aim 1 and then are trained to self-administer METH as adults, followed by assessment of PV neurons, PNNs and their components. We predict that groups that were previously exposed as adolescents will exhibit greater escalation of intake and heightened motivation for METH that will be associated with greater increases in PNN expression, with the early adolescent-exposed females being most affected. The studies outlined here provide new avenues for future research on the impact of drug exposure during adolescence and its effects on the structure of the mPFC and later behavior, which in turn may inform the development of new treatment strategies.

项目摘要青春期是一个广泛的神经重组的时期，尤其是在两个人的前额叶皮层中和啮齿动物。内侧前额叶皮层中发生的主要变化之一是增加会内神经元网（PNNS），一种优先围绕Parvalbumin（PV）表达的细胞外基质抑制性中间神经元，增加稳定性和功能支持。我们最近的数据表明，雌性大鼠有雄性不会减少青春期的PNN，这可能会导致女性更大的药物脆弱性青春期和青春期的暴露。当前建议的前提是神经的过程快速加速，抑制性PV中间神经元以及PNN及其成分的成熟内侧前额叶皮层是青春期易用药物使用障碍的重要组成部分。这将通过暴露于高度滥用的药物，甲基苯丙胺（甲基苯丙胺）测试。 AIM 1将确定当甲基甲基暴露对PV神经元和PNN的强度的短期影响时在三个单独的时间点进行管理：早期（与女性青春期重叠），晚期青春期（雄性青春期）或年轻成年。 PV神经元，PNN及其硫酸软骨素蛋白聚糖成分将立即量化，并记录在青春期状态。我们假设这一点 PV强度，PNN的数量及其组件都会下降与年轻成人暴露的增加相比，青少年暴露的前额叶。这种效果会表示可塑性增加，并导致青春期甲基甲基甲基苯丙胺暴露的脆弱性。我们预测青少年青春期的女性，青春期群体将受到最大的影响。 AIM 2将测试动物已在AIM 1中暴露于Meth中评估PV神经元，PNN及其成分。我们预测以前暴露的群体因为青少年将表现出更大的摄入量和甲基苯丙胺动机的升级与PNN表达的增加相关，早期暴露于青少年的女性是大多数做作的。此处概述的研究为未来研究药物暴露的影响提供了新的途径在青春期及其对MPFC结构的影响和后来的行为，这又可能告知开发新的治疗策略。