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

• 批准号: 10669275
• 负责人: Joshua M Gulley
• 金额: $ 17.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 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/10669275
• 关键词: Address; Adolescence; Adolescent; Adolescent Development; Adult; Affect; Age; 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; neural circuit; neuromechanism; novel therapeutic intervention; sex; small hairpin RNA; stimulant use; substance use; versican; vulnerable adolescent; young adult

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 青春期是广泛的神经重组时期，尤其是在两人的前额叶皮质。 还有啮齿动物。发生在内侧前额叶皮质的主要变化之一是 神经周围神经网络(PNNS)，一种优先围绕表达小白蛋白(PV)的细胞外基质 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，雌性老鼠有一种 青春期的PNN减少，而男性不会，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。目前提议的前提是，神经的过程 大鼠脑室旁核快速放电抑制性中间神经元的成熟及PNN及其成分的形成 内侧前额叶皮质是青春期易受物质使用障碍影响的重要组成部分。 这将在接触高度滥用的药物甲基苯丙胺(冰毒)的情况下进行测试。目标一号将决定 冰毒暴露对大鼠下丘脑室旁核和黑质神经元数量和强度的短期影响 在三个不同的时间点给药：青春期早期(与女性青春期重叠)，晚期- 青春期(男性青春期)，或青春期。PV神经元、PNNS及其硫酸软骨素 蛋白多糖成分将立即进行量化，并记录青春期状态。我们假设 在内侧，PV强度、PNN数量及其组件都将减少 暴露在前额叶的青少年，与暴露在青壮年的增加相比。这一效果将 表明青春期的可塑性增加和由此导致的对冰毒暴露的脆弱性。我们 预测女性在青春期、青春期人群中受影响最大。Aim 2将测试动物 在AIM 1中接触过冰毒，然后在成年后接受自我注射冰毒的培训，然后是 对PV神经元、PNN及其成分进行评估。我们预测，之前接触过的群体 由于青少年将表现出更大的摄入量升级和对冰毒的强烈动机，这将是 与PNN表达的更大增加有关，早期青春期暴露的女性最多 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的途径 在青春期及其对mPFC结构和后来的行为的影响，这反过来可能会告知 开发新的治疗策略。