The functional significance of exercise-induced neurogenesis in cocaine reward

描述(由申请者提供)：有氧运动和药物滥用之间的相互作用相对未被探索。它值得关注，因为最近的数据表明，运动中的神经适应促进了与药物滥用重叠的回路中的学习。海马体是一个重要的交叉点，因为它是有氧运动改变的主要场所，在情境调节中起着核心作用。具体地说，与毒品配对的背景线索会触发与渴望和复发相关的情绪反应。该研究计划的长期目标是确定运动对小鼠药物相关行为影响的分子和生理机制。这项应用的总体目标是建立一个小鼠模型来研究轮跑运动对可卡因条件性位置偏爱消退的影响，并测试运动如何影响巴甫洛夫药物联系的一个假想机制。中心假设是，如果在新神经元发育的关键时期给药，运动产生的新神经元可以导致药物联系持续存在，因为新神经元优先被招募到学习网络中。这得到了初步研究的支持，该研究表明，与在环境中再次暴露于可卡因后的久坐动物相比，跑步者对可卡因的条件反射偏好对消退具有抵抗力。这项申请的目标将通过追求两个具体目标来实现。目的1是确定有氧运动对消除条件性场所偏爱可卡因的影响。基于初步研究，工作假设是，运动将促进或推迟条件性位置偏好的消退，这取决于药物暴露是在运动训练之前还是之后发生的，同时伴随着成年海马齿状回神经发生的增加。为了达到这一目的，条件反射和运动治疗的顺序将被操纵，然后条件反射位置偏好将被重复测量，直到消失。将向动物注射BrdU以标记分裂细胞，并将使用齿状回颗粒层中与神经元核标记Neun共同标记的BrdU细胞数量来衡量神经发生。目的2是确定运动产生的新神经元在多大程度上促进了对可卡因的条件性位置偏爱的持续。在初步研究的基础上，工作假设是运动产生的新神经元将发挥增强巴甫洛夫条件反射的功能。这一假说将通过使用两种不同的方法减少神经发生来直接检验，这两种方法是转基因小鼠模型和局部伽马照射，以确定运动是否需要新的神经元来延缓位置偏好的消退。新神经元优先招募到参与可卡因调节的回路的程度也将通过测量BrdU阳性细胞与阴性细胞对偏好测试的反应而表达c-Fos的比例来确定。该项目将发现运动和药物滥用之间的相互作用机制。这将有助于评估将锻炼纳入药物滥用治疗的好处或风险。 公共卫生相关性：这项建议将在小鼠模型中发现有氧运动增强的神经可塑性对可卡因条件性行为消退的影响。该项目将为评估将锻炼纳入药物滥用治疗的益处或风险提供有用的证据。

DESCRIPTION (provided by applicant): The interaction between aerobic exercise and drug abuse is relatively unexplored. It deserves attention because recent data suggest neuroadaptations from exercise promote learning in circuits that overlap with drug abuse. The hippocampus is an important point of intersection because it is a major locus for change from aerobic exercise and it plays a central role in contextual conditioning. Specifically, contextual cues paired with drugs trigger emotional responses related to craving and relapse. The long-term goal of this research program is to identify molecular and physiological mechanisms underlying the influence of exercise on drug-related behaviors in mice. The overall objective of this application is to develop a mouse model to study the effects of wheel running exercise on extinction of cocaine conditioned place preference, and to test one hypothesized mechanism for how exercise can influence Pavlovian drug associations. The central hypothesis is that new neurons from exercise can cause drug associations to persist if the drug is administered at a critical period in the development of the new neurons when they are preferentially recruited into learning networks. This is supported by the Preliminary Studies that show resistance to extinction of conditioned place preference for cocaine in runners as compared to sedentary animals after re-exposure to cocaine in context. The objective of this application will be accomplished by pursuing two specific aims. Aim 1 is to identify the impact of aerobic exercise on extinction of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that exercise will either facilitate or delay extinction of conditioned place preference depending on whether drug exposure occurs before or after exercise training, in parallel with increased adult hippocampal neurogenesis in the dentate gyrus. To accomplish this aim, the order of conditioning and exercise treatments will be manipulated, and then conditioned place preference will be measured repeatedly until extinction. Animals will be injected with BrdU to label dividing cells, and the number of BrdU cells co-labeled with neuronal nuclear marker, NeuN, in the granule layer of the dentate gyrus will be used to measure neurogenesis. Aim 2 is to determine the extent to which new neurons from exercise causally contribute to persistence of conditioned place preference for cocaine. Based on Preliminary Studies, the working hypothesis is that new neurons from exercise will function to enhance Pavlovian conditioning. This hypothesis will be directly tested by reducing neurogenesis using 2 separate methods, a transgenic mouse model and focal gamma irradiation, to determine whether new neurons are required for exercise to delay extinction of place preference. The extent to which new neurons are preferentially recruited into circuits involved in cocaine conditioning will also be determined by measuring the proportion of BrdU positive versus negative cells expressing c-Fos in response to the preference test. The project will discover mechanisms for interactions between exercise and drug abuse. This will be useful for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse. PUBLIC HEALTH RELEVANCE: This proposal will discover the impact of enhanced neuroplasticity from aerobic exercise on extinction of cocaine conditioned behavior in a mouse model. The project will provide useful evidence for evaluating the benefits or risks of incorporating exercise in treatment of drug abuse.