Guidance molecules interact to orchestrate dopamine plasticity in adulthood

大脑的多巴胺系统参与认知、运动活动、动机和奖励。这些系统及其连接具有显着的可塑性，在一生中都会发生变化。反复接触安非他明等兴奋剂药物会导致多巴胺系统发生变化，从而导致对这些药物以及激活多巴胺系统的其他生活事件的敏感性长期持续增加。我的研究项目的总体目标是确定导致成年期多巴胺功能和行为敏感性发生变化的机制，使个体更容易（或更少）容易受到随后接触药物或压力源的影响。为此，我将研究安非他明如何在成人大脑中引起这种变化。这些过程的识别将对我们理解“经验”如何改变多巴胺回路，进而改变多巴胺介导的行为产生重要影响。成人大脑中多巴胺系统变化的持久性表明，通过重新激活通常参与发育过程中组织神经元接线的因子来重组电路。 Netrin-1 是一种在发育过程中神经元连接组织中发挥重要作用的蛋白质，我们最近发现 (1) netrin-1 受体在成人大脑中的多巴胺神经元中高度表达，(2) 成人反复接触安非他明会上调 netrin-1 受体的表达，(3) 安非他明对 netrin-1 受体的上调是安非他明诱导的多巴胺可塑性发育所必需的。该研究计划现旨在确定 netrin-1 和 netrin-1 受体如何精确地介导成人中安非他明诱导的多巴胺可塑性。**

The dopamine systems of the brain are involved in cognition, motor activity, motivation and reward. These systems and their connections are remarkably plastic, undergoing changes throughout life. Repeated exposure to stimulant drugs, such as amphetamine, results in changes in dopamine systems resulting in long-lasting increases in sensitivity to the effects that these drugs, and to other life events that activate the dopamine systems. The general aim of my research project is to identify mechanisms that bring about changes in sensitivity in dopamine function and behavior in adulthood, rendering individuals more (or less) vulnerable to subsequent exposure to drugs or to stressors. To this end I will study how amphetamine induces such changes in the adult brain. Identification of these processes will have important implications for our understanding of how `experience' can alter dopamine circuitry and, in turn, dopamine-mediated behaviors. The enduring nature of changes in the dopamine system in the adult brain suggests reorganization of the circuitry by re-activation of factors that are normally involved in organizing neuronal wiring during development. Netrin-1 is a protein that plays a fundamental role in the organization of neuronal connectivity during development and we have recently shown that (1) netrin-1 receptors are highly expressed by dopamine neurons in the adult brain, (2) repeated amphetamine exposure in the adult upregulates the expression of netrin-1 receptors, (3) netrin-1 receptor upregulation by amphetamine is required for the development of amphetamine induced dopamine plasticity. This research proposal is now aimed at identifying how precisely netrin-1 and netrin-1 receptors mediate amphetamine-induced dopamine plasticity in the adult.**