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尚未被探索。这一点值得关注，因为最近的数据表明，运动带来的神经适应促进了与药物滥用重叠的神经回路的学习。海马体是一个重要的交叉点，因为它是有氧运动变化的主要位点，在环境条件反射中起着核心作用。具体来说，情境线索与药物配对会引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。本应用程序的总体目标是建立一个小鼠模型，研究滚轮跑步运动对可卡因条件位置偏好消退的影响，并测试运动如何影响巴甫洛夫药物关联的一种假设机制。核心假设是，如果在新神经元发育的关键时期给药，当它们优先被吸收到学习网络中时，运动产生的新神经元会导致药物关联持续存在。初步研究表明，与久坐不动的动物相比，跑步者在再次暴露于可卡因环境后，对可卡因的条件性位置偏好的消失具有抵抗力。此应用程序的目标将通过追求两个具体目标来实现。目的1是确定有氧运动对可卡因条件位置偏好消失的影响。基于初步研究，工作假设是，运动将促进或延迟条件位置偏好的消退，这取决于药物暴露是发生在运动训练之前还是之后，与此同时，成人海马齿状回神经发生增加。为了达到这一目的，我们将操纵条件反射和运动治疗的顺序，然后反复测量条件反射的位置偏好，直到消失。给动物注射BrdU标记分裂细胞，在齿状回颗粒层用BrdU与神经元核标记物NeuN共标记的细胞数来测量神经发生。目的2是确定运动产生的新神经元在多大程度上促成了可卡因条件位置偏好的持续存在。根据初步研究，工作假设是运动产生的新神经元将增强巴甫洛夫条件反射。这一假设将通过使用两种不同的方法（转基因小鼠模型和局灶伽马辐射）减少神经发生来直接验证，以确定运动是否需要新的神经元来延迟位置偏好的消失。新神经元在多大程度上被优先招募到涉及可卡因条件作用的回路中，也将通过测量BrdU阳性与阴性细胞在响应偏好测试时表达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。

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.