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

摘要： 众所周知，每个人对药物的耐受性和上瘾倾向都不同，而且 这些特征是高度可遗传的，是许多等位基因相互作用的结果。这种多基因遗传性使 诊断易感性和有针对性的治疗比单基因疾病更困难。尽管有浩瀚的 基因异质性，有滥用和成瘾的核心原则，为新的 治疗：所有滥用药物都是通过上调多巴胺信号获得享乐性的，并且 反复暴露后多巴胺能回路的改变是成瘾的根本原因。因此，它是 可能许多相关的遗传易感基因与多巴胺反应的调节有关 毒品和触发情况。如果我们改进我们精确操纵多巴胺能回路的能力，我们将 能够设计治疗方法来对抗虐待和成瘾的原因，这是为个人量身定做的， 而不一定需要纠正因果等位基因。学习的重要性和潜力 对抗成瘾的多巴胺能控制系统早就被认识到了；我提出了一种新的、有前途的 快速识别多巴胺能调节的回路和分子原理的方法。 我的实验室最近建立了两个新的系统来研究动机的多巴胺能控制 行为。在这些系统中，两组不同的多巴胺能神经元提供动态的动力 黑腹果蝇雄性交配行为的两个不同方面：求偶和交配。 控制这些行为的少量多巴胺能神经元嵌入在神经元中 精确调节多巴胺释放量的网络，使动机水平与 行为目标的相关性。我们研究这些行为是因为i)它们显示出明显的特征 多巴胺能调节动机；ii)它们是健壮的、明确的、容易量化的；iii) 潜在的神经元是可识别的，并通过它们的性二型性表达而在基因上可获得 果蝇的研究历史表明，我们发现的原理将适用于哺乳动物。 这项工作的主要目标是为干预措施产生新的假设和药物靶点，以防止 药物成瘾的开始和持续。新的动机调节因子的表征 多巴胺能回路也将用于识别滥用和成瘾的高危人群。 在这些基因座上有改变的等位基因。 这个项目是创新的，因为它在一个简单的模型中结合了电路和分子方法 系统，以快速识别与行为相关的多巴胺能活动调节器。我不相信有任何 这种方法以前就曾被采用过，因此它有望带来新的发现和治疗的潜力。 和诊断学。

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.