Mating behavior in Drosophila as a model for understanding and controlling aberrant dopaminergic responses

总结： 众所周知，个体在药物耐受性和成瘾倾向方面存在差异， 这些性状是高度遗传的，是许多等位基因相互作用的结果。这种多基因遗传性使得 诊断易感性和靶向治疗比单基因疾病更困难。尽管巨大的 遗传异质性，有滥用和成瘾的核心原则，提供了新的可能性 治疗：所有滥用的药物都是通过上调多巴胺信号来获得快感的， 反复接触后多巴胺能回路的改变是成瘾的根本原因。因此 可能许多相关的遗传易感性位点参与多巴胺反应的调节， 毒品和触发事件如果我们能够精确地控制多巴胺能神经回路， 能够设计治疗方法来对抗针对个人的滥用和成瘾的原因， 而不必校正致病等位基因。学习的重要性和潜力 多巴胺能控制系统，以打击成瘾早已认识到，我提出了一个新的和有前途的 方法来快速识别多巴胺能调节的电路和分子原理。 我的实验室最近建立了两个新的系统来研究多巴胺能控制的动机 行为在这些系统中，两个独立的多巴胺能神经元群体提供动态激励。 输入到两个不同方面的雄性交配行为在果蝇：求偶和交配。 控制这些行为的多巴胺能神经元的小群体嵌入神经元内。 网络，精确地调整多巴胺的释放量，使动机的水平匹配 行为目标的相关性。我们研究这些行为是因为i）它们显示出 动机的多巴胺能调节; ii）它们是稳健的，明确的，并且容易量化; iii） 潜在的神经元是可识别的，并通过它们的性二态性表达遗传上可接近的。 基因;和iv）在果蝇中的工作历史表明，我们发现的原则将适用于哺乳动物。 这项工作的主要目标是产生新的假设和干预药物靶点， 毒瘾的发作和持续新的动机调节因子的表征 多巴胺能回路也将用于识别高风险的滥用和成瘾的人，通过他们的神经系统。 在这些基因座上拥有改变的等位基因。 这个项目是创新的，因为它结合了电路和分子的方法在一个简单的模型 快速识别多巴胺能活性的行为相关调节剂的系统。我不相信任何 这种方法以前曾被采用过，因此它有可能带来新的发现和治疗潜力 和诊断。

Summary: It is well known that individuals differ in drug tolerance and propensity for addiction, and that both of these traits are highly heritable, resulting from interactions of many alleles. This multi-genic heritability makes diagnosing susceptibility and targeted treatment more difficult than for monogenic disorders. Despite the vast genetic heterogeneity, there are core principles of abuse and addiction that provide possibilities for new treatments: all drugs of abuse derive their hedonic qualities by upregulating dopamine signaling, and alterations in dopaminergic circuitry following repeated exposure are the root cause of addiction. It is therefore likely that many of the relevant genetic susceptibility loci are involved in the regulation of dopamine responses to drugs and triggering situations. If we refine our ability to precisely manipulate dopaminergic circuitry, we will be able to design treatments to counter the causes of abuse and addiction that are tailored to the individual, without necessarily needing to correct the causal alleles. The importance and potential of studying dopaminergic control systems to combat addiction have long been recognized; I propose a new and promising approach to rapidly identify the circuit and molecular principles of dopaminergic regulation. My lab has recently established two new systems for studying dopaminergic control of motivated behavior. In these systems, two separate populations of dopaminergic neurons provide dynamic motivational input into two distinct aspects of male mating behavior in Drosophila melanogaster: courtship and copulation. The small populations of dopaminergic neurons that control these behaviors are embedded within neural networks that precisely tune the amount of dopamine released so that the level of motivation matches the relevance of the behavioral goals. We study these behaviors because i) they show clear hallmarks of dopaminergic regulation of motivation; ii) they are robust, unambiguous, and easily quantified; iii) the underlying neurons are identifiable and genetically accessible through their expression of sexually dimorphic genes; and iv) the history of work in Drosophila suggests that the principles we uncover will apply to mammals. The main goal of this work is to generate new hypotheses and drug targets for interventions that will prevent the onset and persistence of drug addiction. The characterization of novel regulators of motivational dopaminergic circuitry will also be of use in identifying people at high-risk for abuse and addiction through their possession of altered alleles at these loci. This project is innovative because it combines circuit and molecular approaches in a simple model system to rapidly identify behaviorally-relevant regulators of dopaminergic activity. I do not believe that any such approach has been taken before and it therefore promises new discoveries and potential for treatments and diagnostics.