Intersecting genetic risk for extreme cocaine self-administration with dopamine neurotransmission

项目摘要/摘要 可卡因使用障碍是一种复杂的、可遗传的特征，会对患者造成重大伤害。 对社会的影响。发现影响可卡因使用障碍风险的遗传因素对于 全面了解可卡因成瘾的神经生物学。在一项正在进行的研究中，我们描述了 一大批近亲交配的小鼠品系，用于自愿给药(IVSA)。我们正在利用这一点 一种识别影响可卡因自我给药的基因和等位基因变异的方法，包括神经元- Navigator-1(NAV1)，这是从我们的遗传分析中出现的一个候选基因。此外，近亲交配 HMDP中易服用大量可卡因的参考菌株代表多基因 极端使用可卡因的模型，可以用来理解风险变量如何共同影响 神经生物学最终影响可卡因的自我给药。这里提出的项目将直接调查 极端可卡因IVSA遗传风险对中脑边缘多巴胺的多基因和单基因影响 神经传递，一种关键的神经生物学功能，受到可卡因和其他滥用药物的影响。这个项目 将提供快速扫描循环伏安法、光遗传学和纤维光度学方面的培训，并将使我能够 在成瘾神经遗传学研究中创造独特的利基市场。目标1将调查多基因风险的影响 极端可卡因静脉注射对急性发作后伏核(NAC)壳多巴胺神经传递的影响 可卡因的应用。这一目标可能揭示基因对基础和急性多巴胺反应的影响 这是可卡因使用失控的潜在风险。目标2将调查多基因风险对极端情况的影响 可卡因IVSA对慢性可卡因IVSA后NAC多巴胺传递的神经适应作用 曝光。这一目的可能揭示基因决定的多巴胺传递的适应 在长期接触后逐步增加使用。目标3将评估实验中NAV1变化的因果效应 多巴胺传递在单基因水平的表达。这个项目将促进对如何 遗传学与神经生物学交叉影响可卡因的使用。我在执行这个项目时将接受的培训 将拓宽我的技能范围，使我能够更有效地研究成瘾神经遗传学。

Project summary/abstract Cocaine use disorder is a complexly determined, heritable trait that imposes significant harm on those afflicted and on society. Discovery of the genetic factors that influence cocaine use disorder risk is imperative for a comprehensive understanding of cocaine addiction neurobiology. In an ongoing study, we have characterized a large panel of inbred mouse lines for voluntary cocaine self-administration (IVSA). We are utilizing this approach to identify genes and allelic variants that influence cocaine self-administration, including Neuron- navigator-1 (Nav1), which has emerged as a candidate gene from our genetic analyses. Furthermore, inbred reference strains in the HMDP that are predisposed to take large amounts of cocaine represent polygenic models of extreme cocaine use and can be used to understand how risk variants collectively impact neurobiology to ultimately affect cocaine self-administration. The project proposed here will directly investigate the polygenic and single gene impact of genetic risk for extreme cocaine IVSA on mesolimbic dopamine neurotransmission, a key neurobiological function impacted by cocaine and other drugs of abuse. This project will provide training in fast-scan cyclic voltammetry, optogenetics and fiber photometry and will allow me to create a unique niche in addiction neurogenetics research. Aim 1 will investigate the influence of polygenic risk for extreme cocaine IVSA on dopamine neurotransmission in the Nucleus Accumbens (NAc) shell after acute application of cocaine. This aim may reveal genetic influences on basal and acute dopamine responses that underlie risk for dysregulated cocaine use. Aim 2 will investigate the influence of polygenic risk for extreme cocaine IVSA on neuroadaptations in dopamine transmission in the NAc following chronic cocaine IVSA exposure. This aim may reveal genetically determined adaptations of dopamine transmission that underlie escalated use after chronic exposure. Aim 3 will evaluate the causal effects of experimental changes in Nav1 expression on dopamine transmission at the single-gene level. This project will advance understanding of how genetics intersect with neurobiology to affect cocaine use. The training I will receive in conducting this project will broaden my skill set and allow me to more effectively investigate addiction neurogenetics.