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

项目概要/摘要 强迫症是一种复杂的决定性遗传特征，对患者造成重大伤害 和社会。发现影响可卡因使用障碍风险的遗传因素对于研究可卡因使用障碍的风险至关重要。 对可卡因成瘾神经生物学的全面了解。在一项正在进行的研究中，我们描述了 一个大的小组近交系小鼠自愿可卡因自我管理（IVSA）。我们正在利用这个 确定影响可卡因自我给药的基因和等位基因变体的方法，包括神经元- navigator-1（Nav 1），它已经成为我们遗传分析的候选基因。此外，Inbred HMDP中倾向于服用大量可卡因的参考菌株代表多基因 极端可卡因使用的模型，并可用于了解风险变量如何共同影响 最终影响可卡因自我给药。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 神经传递是受可卡因和其他滥用药物影响的关键神经生物学功能。这个项目 将提供快速扫描循环伏安法，光遗传学和光纤光度学的培训，并将允许我 在成瘾神经遗传学研究中创造一个独特的利基。目的1将研究多基因风险的影响 极端可卡因IVSA对急性后伏隔核（NAc）壳多巴胺神经传递的影响 可卡因的应用。这一目标可能揭示遗传对基础和急性多巴胺反应的影响， 是可卡因使用失调的潜在风险。目的2将研究多基因风险对极端 可卡因IVSA对慢性可卡因IVSA后NAc中多巴胺传递的神经适应的影响 exposure.这一目标可能揭示遗传决定的多巴胺传递适应， 在慢性暴露后逐步增加使用。目的3将评估Nav 1实验变化的因果效应 在单基因水平上对多巴胺传递的影响。该项目将促进了解如何 遗传学与神经生物学交叉影响可卡因的使用。我将接受的培训在进行这个项目 这将拓宽我的技能，让我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.