Amphetamine During Adolescence Reroutes Mesolimbic Dopamine Axons to the Prefrontal Cortex via DCC Signaling

 描述（由申请人提供）：青少年是个人最有可能开始滥用药物的时期。然而，在青春期开始使用毒品也是从娱乐性使用发展成成瘾的最高风险。这表明，在青春期的关键窗口期暴露于药物可能会干扰正在进行的神经元发育，并导致行为变化，从而促进随后的药物滥用和成瘾。然而，仍然是一个显着缺乏知识的机制占这些年龄依赖性的影响，药物暴露。为了解决我们知识中的这一差距，重要的是要了解（1）滥用药物与青少年大脑之间相互作用的机制，（2）这些相互作用如何破坏神经元回路的发育，以及（3）成瘾相关行为的长期变化。最近出现的指导提示受体DCC作为一个关键的分子球员在青春期组织的mesocorticolimbic多巴胺系统，DCC的表达是受青少年暴露于滥用药物。在青春期早期暴露于滥用的兴奋剂安非他明，通过改变DCC信号传导破坏了小鼠内侧前额叶皮层多巴胺输入的发育。本文提出的研究的长期目标是确定青春期安非他明是否通过破坏DCC介导的指导事件将多巴胺轴突从边缘区重新路由到内侧前额叶皮层，并确定对前额叶皮层依赖性认知行为的持久后果。这些神经生物学和行为学的改变可能是在青春期开始使用药物的个体更容易成瘾的基础。这些实验将在小鼠模型中采用神经解剖学、基因转染和行为技术来评估三个特定目标。目的1将确定是否安非他明在青春期增加前额叶皮层多巴胺神经支配，促进中脑边缘多巴胺轴突在青春期的重新路由。目的2将评估DCC信号传导是否是青春期安非他明将中脑边缘多巴胺轴突重新路由到前额皮质的分子机制。目的3将确定DCC在介导青少年中脑皮质边缘多巴胺重组的长期行为后果中的作用。 这项研究的结果将使该领域更清楚地了解药物暴露对成瘾脆弱性的年龄依赖性影响的机制。这些结果可用于促进针对青少年吸毒者的个性化预防和治疗策略的制定，这些青少年吸毒者面临着更高的成瘾风险。

 DESCRIPTION (provided by applicant): Adolescence is the period in which individuals are most likely to initiate the consumption of drugs of abuse. The onset of drug use during adolescence, however, also confers the highest risk of progressing from recreational use to addiction. This suggests that drug exposure during the critical window of adolescence may interfere with ongoing neuronal development and cause behavioral changes which facilitate subsequent substance abuse and addiction. However, there is still a significant lack of knowledge about the mechanisms accounting for these age-dependent effects of drug exposure. To address this gap in our knowledge, it is important to understand (1) the mechanism underlying the interaction between drugs of abuse and the adolescent brain, (2) how these interactions disrupt the development of neuronal circuitry, and (3) the resulting long-lasting changes in addiction-relevant behaviors. The guidance cue receptor DCC has recently emerged as a key molecular player in the adolescent organization of the mesocorticolimbic dopamine system, and expression of DCC is regulated by adolescent exposure to drugs of abuse. Exposure to the stimulant drug of abuse, amphetamine, during early adolescence disrupts the development of dopamine input to the medial prefrontal cortex of mice via alterations to DCC signaling. The long-term goal of the studies proposed here is to determine if amphetamine in adolescence reroutes dopamine axons to the medial prefrontal cortex from limbic regions by disrupting DCC-mediated guidance events, and identify the enduring consequences on prefrontal cortex-dependent cognitive behavior. These neurobiological and behavioral alterations may underlie heightened vulnerability to progress to addiction in individuals that initiate drug use in adolescence. The experiments will employ neuroanatomical, gene transfection, and behavioral techniques in a mouse model to assess three specific aims. Aim 1 will determine whether amphetamine in adolescence increases prefrontal cortex dopamine innervation by promoting the rerouting of mesolimbic dopamine axons during adolescence. Aim 2 will assess whether DCC signaling is the molecular mechanism by which amphetamine in adolescence reroutes mesolimbic dopamine axons to the prefrontal cortex. Aim 3 will determine the role of DCC in mediating the long-term behavioral consequences of adolescent mesocorticolimbic dopamine reorganization. The results of the proposed research will move the field toward a clearer understanding of the mechanisms accounting for the age-dependent effects of drug exposure on addiction vulnerability. These results could be used to facilitate development of individualized prevention and treatment strategies aimed at adolescent drug users, who are at heightened risk to progress to addiction.