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

项目摘要 青春期是一个广泛的神经重组的时期，特别是在人类的前额叶皮层 和啮齿动物。发生在内侧前额叶皮层的一个主要变化是， 神经元周网（PNN），一种细胞外基质，优先围绕小白蛋白（PV）表达 抑制中间神经元，增加稳定性和功能支持。我们最近的数据显示，雌性大鼠有一个 青春期PNN减少，男性不会，这可能导致女性更容易受到药物的影响。 在青春期和青春期暴露。目前建议的前提是，神经过程 快速尖峰，抑制PV中间神经元的成熟，以及PNN及其组分的形成， 内侧前额叶皮层是青春期易受物质使用障碍影响的重要部分。 这将通过接触高度滥用的药物甲基苯丙胺（METH）进行测试。目标1将决定 METH暴露对PV神经元和PNN的数量和强度的短期影响， 在三个不同的时间点施用：青春期早期（与女性青春期重叠）， 青春期（男性青春期）或青年期。PV神经元、PNN及其硫酸软骨素 蛋白多糖组分将在记录青春期状态后立即定量。我们假设 在内侧，PV强度、PNN的数量及其分量都将减少， 前额叶的暴露，相比之下，增加年轻的成年人暴露。这种效应会 表明可塑性的增加和由此产生的对青春期接触甲基苯丙胺的脆弱性。我们 预测处于青春期的女性，青春期组将受到最大的影响。目标2将测试动物， 在目标1中暴露于甲基苯丙胺，然后接受成人自我施用甲基苯丙胺的培训， 评估PV神经元、PNN及其组分。我们预测那些之前接触过 因为青少年将表现出更大的摄入量升级和更高的动机甲基，这将是 与PNN表达的更大增加相关，早期暴露于前列腺素的女性最多， 影响。这里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的结构和以后的行为的影响，这反过来又可以告知 开发新的治疗策略。

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.