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

项目概要 青春期是一个广泛的神经重组的时期，尤其是在人类的前额皮质中 和啮齿动物。内侧前额叶皮质发生的主要变化之一是 神经元周围网 (PNN)，一种优先围绕小清蛋白 (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，雌性老鼠有 青春期时 PNN 减少，而男性则不会，这可能导致女性更容易受到毒品影响 青春期和青春期的暴露。当前提议的前提是神经网络的过程 快速尖峰、抑制性 PV 中间神经元的成熟，以及 PNN 及其组件的形成 内侧前额叶皮层是青春期容易遭受药物滥用障碍的重要组成部分。 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 冰毒暴露对 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进行给药：青春期早期（与女性青春期重叠）、晚期 青春期（男性青春期）或成年初期。 PV 神经元、PNN 及其硫酸软骨素 蛋白多糖成分将立即量化并记录青春期状态。我们假设 内侧的 PV 强度、PNN 及其组件的数量都会减少 与年轻人相比，青少年暴露的前额叶有所增加。这种效果会 表明青春期可塑性的增加以及由此导致的冰毒暴露的脆弱性。我们 预测处于青春期的女性，青春期群体将受影响最大。目标 2 将测试动物 在目标 1 中接触过冰毒，然后接受成人自我管理冰毒的培训，然后 PV 神经元、PNN 及其组件的评估。我们预测之前接触过的群体 因为青少年将表现出更大的摄入量和对冰毒的更高的动机，这将是 与 PNN 表达的更大增加相关，其中青少年早期暴露的女性最为常见 受影响。这里概述的研究为未来研究药物暴露的影响提供了新途径 青春期期间及其对 mPFC 结构和后来行为的影响，这反过来可能会提供信息 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.