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

果蝇的交配行为作为理解和控制异常多巴胺能反应的模型

• 批准号: 10221658
• 负责人: Michael A Crickmore
• 金额: $ 53.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221658
• 关键词: Alleles; Behavior Control; Behavioral; Biological Models; Copulation; Courtship; Diagnosis; Diagnostic; Dopamine; Drosophila genus; Drosophila melanogaster; Drug Addiction; Drug Targeting; Drug Tolerance; Genes; Genetic Heterogeneity; Genetic Predisposition to Disease; Goals; Heritability; Individual; Intervention; Mammals; Mendelian disorder; Modeling; Molecular; Motivation; Mutation; Narcotics; Neurons; Patients; Pharmaceutical Preparations; Plant Roots; Population; Predisposition; Recording of previous events; Regulation; Signal Transduction; Susceptibility Gene; System; Work; addiction; behavioral study; causal variant; combat; dopaminergic neuron; drug of abuse; hedonic; high risk; innovation; male; mating behavior; motivated behavior; neural network; new therapeutic target; novel; prevent; response; sexual dimorphism; targeted treatment; therapy design; trait

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.

概括： 众所周知，个体在药物耐受性和成瘾倾向方面有所不同，并且两者都 这些特征是由于许多等位基因的互动而产生的。这种多生的遗传力使 诊断敏感性和靶向治疗比单基因疾病更加困难。尽管很大 遗传异质性，有虐待和成瘾的核心原则为新的可能性提供了可能性 治疗：所有虐待药物都通过上调多巴胺信号传导而获得其享乐品质，并且 反复暴露后多巴胺能回路的改变是成瘾的根本原因。因此是 许多相关的遗传易感基因座可能参与多巴胺反应的调节 毒品和触发情况。如果我们完善了精确操纵多巴胺能电路的能力，我们将 能够设计治疗方法以应对针对个人量身定制的虐待和成瘾的原因， 不必纠正因果等位基因。学习的重要性和潜力 长期以来，已经认识到要打击成瘾的多巴胺能控制系统。我提出了一个新的有前途的 快速识别多巴胺能调节的电路和分子原理的方法。 我的实验室最近建立了两个用于研究动机多巴胺能控制的新系统 行为。在这些系统中，两个单独的多巴胺能神经元种群提供了动态动机 输入果蝇中男性交配行为的两个不同方面：求爱和交配。 控制这些行为的多巴胺能神经元的少量嵌入在神经中 精确调整多巴胺量释放的网络，以使动机水平与 行为目标的相关性。我们研究这些行为，因为i）它们显示出明确的标志 多巴胺能调节动机； ii）它们是坚固的，明确的，并且容易量化； iii） 潜在的神经元可以通过性表达二态性来识别和遗传访问 基因； iv）果蝇的工作历史表明，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为干预措施产生新的假设和药物目标 吸毒成瘾的发作和持久性。动机的新型监管机构的特征 多巴胺能电路也将用于识别高风险的人，以滥用和成瘾 在这些基因座中拥有改变等位基因。 该项目具有创新性，因为它结合了简单模型中的电路和分子方法 系统以快速识别与行为相关的多巴胺能活性调节剂。我不相信任何 以前已经采取了这种方法，因此有望有新的发现和治疗潜力 和诊断。

项目成果

Recurrent Circuitry Sustains Drosophila Courtship Drive While Priming Itself for Satiety.

循环回路维持果蝇的求偶冲动，同时为自身做好饱腹感的准备。

• DOI: 10.1016/j.cub.2019.08.015
• 发表时间: 2019
• 期刊: Current biology : CB
• 作者: Zhang,StephenX;Rogulja,Dragana;Crickmore,MichaelA
• 通讯作者: Crickmore,MichaelA

Hormonal control of motivational circuitry orchestrates the transition to sexuality in Drosophila.

• DOI: 10.1126/sciadv.abg6926
• 发表时间: 2021-06
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Zhang SX;Glantz EH;Miner LE;Rogulja D;Crickmore MA
• 通讯作者: Crickmore MA

Motivation, Perception, and Chance Converge to Make a Binary Decision.

动机、感知和机会汇聚在一起做出二元决定。

• DOI: 10.1016/j.neuron.2018.06.014
• 发表时间: 2018
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Zhang,StephenX;Miner,LaurenE;Boutros,ChristineL;Rogulja,Dragana;Crickmore,MichaelA
• 通讯作者: Crickmore,MichaelA