The functional significance of exercise-induced neurogenesis in cocaine reward

描述（由申请人提供）：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，运动引起的神经适应促进了与药物滥用重叠的回路的学习。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部位，并且在环境条件反射中起着核心作用。具体来说，与药物配对的情境线索会触发与渴望和复发相关的情绪反应。这项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。本申请的总体目标是开发一种小鼠模型，以研究转轮跑步运动对可卡因条件性位置偏好消退的影响，并测试一种假设的运动如何影响巴甫洛夫药物关联的机制。核心假设是，如果在新神经元发育的关键时期给予药物，当它们优先被招募到学习网络中时，运动产生的新神经元可以导致药物联合持续存在。这得到了初步研究的支持，初步研究表明，与久坐不动的动物相比，跑步者在重新接触可卡因后，对可卡因的条件位置偏好的消退有抵抗力。本申请的目的将通过追求两个具体目标来实现。目的1是确定有氧运动对可卡因条件性位置偏爱消退的影响。基于初步研究，工作假设是运动将促进或延迟条件性位置偏好的消退，这取决于药物暴露是否发生在运动训练之前或之后，与齿状回中成年海马神经发生的增加平行。为了实现这一目标，条件反射和运动治疗的顺序将被操纵，然后条件位置偏好将被反复测量，直到消失。将给动物注射BrdU以标记分裂细胞，并且将使用齿状回颗粒层中与神经元核标记物NeuN共标记的BrdU细胞的数量来测量神经发生。目的2是确定运动产生的新神经元在多大程度上对可卡因条件性位置偏爱的持续性有因果关系。基于初步研究，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作用。该假设将通过使用2种单独的方法（转基因小鼠模型和局灶性伽马辐照）减少神经发生来直接测试，以确定运动是否需要新的神经元来延迟位置偏好的消退。新神经元优先募集到参与可卡因条件反射的回路中的程度也将通过测量响应于偏好测试的表达c-Fos的BrdU阳性细胞与阴性细胞的比例来确定。该项目将发现运动和药物滥用之间相互作用的机制。这将有助于评估将运动纳入药物滥用治疗的益处或风险。 公共卫生相关性：这项提议将发现有氧运动增强神经可塑性对小鼠模型中可卡因条件行为消退的影响。该项目将为评估将运动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.