Dependence Driven Alterations in Ethanol Reinforcement

INIA联盟U01项目的重点是大脑回路中的遗传差异和神经适应 这是导致个体对过度饮酒易感性存在差异的原因。我们会 使用胃内消耗(IGC)模型来扩展我们之前的发现，在该模型中，几天的 通过慢性胃内插管被动暴露于乙醇(或水)后，进行自我输液 一种测试程序，其中自愿摄取有风味的溶液与IG乙醇配对。此前，我们 发现与乙醇配对的味道(与水配对的味道相比)的IGC和偏好增强 在大鼠和小鼠中都是作为基因的函数而变化的。我们现在提议 主要集中在老鼠身上。目标1将检测两个近交系被动输血阶段的关键参数 菌株C57BL/6J和DBA/2J。这些参数包括：(A)每次输液剂量和每日总剂量；(B) 每日酒精输注次数，以及(C)被动酒精暴露天数。目标2将进一步 解决了遗传差异对依赖驱动的乙醇强化敏感性的假说 将模型扩展到15个标准近交系的IGC特征，允许进行遗传检查 IGC与先前研究的一系列乙醇表型之间的相关性。在来自 INIA科罗拉多基因阵列核心，我们还将检查与整个大脑基因的遗传相关性 表情。目标3将测试被动免疫球蛋白乙醇暴露是否会产生乙醇变化 使用条件位置偏好程序和有限访问操作符的强化/奖励 自治。AIM 4将通过测试两个鼠标模型与其他INIA项目进行协作 为了在狂饮过程中血液中酒精浓度高而有选择地培育的：(A) SHIG和SLAC品系；(B)HDID品系及其遗传控制(HS/NPT)。最后，在来自 INIA神经回路图谱和基因分型核心，AIM 5将使用c-Fos免疫组织化学和 损伤以确定影响被动乙醇后IGC增强的特定脑区 曝光。这个项目的长期目标是了解遗传和神经生物学过程。 过度饮酒是导致人类酗酒的根本原因。通过提高我们的理解 在这些过程中，我们可以确定更有效的治疗和预防战略。

This INIA Consortium U01 Project is focused on genetic differences and neuroadaptations in brain circuitry that are responsible for individual differences in vulnerability to excessive consumption of alcohol. We will extend our previous findings using an intragastric consumption (IGC) model in which several days of passive exposure to ethanol (or water) via a chronic intragastric (IG) cannula are followed by a self-infusion test procedure in which voluntary ingestion of a flavored solution is paired with IG ethanol. Previously, we found that IGC and preference for the ethanol-paired flavor (compared to a water-paired flavor) is enhanced by passive ethanol exposure and varies as a function of genotype in both rats and mice. We now propose to focus primarily on mice. Aim 1 will examine key parameters of the passive infusion phase in two inbred strains, C57BL/6J and DBA/2J. These parameters include: (a) dose per infusion and total daily dose, (b) number of daily ethanol infusions, and (c) number of days of passive ethanol exposure. Aim 2 will further address the hypothesis of genetic differences in sensitivity to dependence-driven ethanol reinforcement by extending the model to characterize IGC in 15 standard inbred strains, allowing examination of genetic correlations between IGC and a wide range of previously studied ethanol phenotypes. With support from the INIA Colorado Gene Array Core, we will also examine genetic correlations with whole brain gene expression. Aim 3 will test whether passive IG ethanol exposure produces changes in ethanol reinforcement/reward using the conditioned place preference procedure and limited access operant self-administration. Aim 4 will involve collaboration with other INIA projects by testing two mouse models that have been selectively bred for high blood ethanol concentrations in binge drinking procedures: (a) the SHAG and SLAC lines, and (b) the HDID line and its genetic control (HS/Npt). Finally, with support from the INIA Neurocircuitry Mapping and Genotyping Core, Aim 5 will use c-Fos immunohistochemistry and lesions to identify specific brain areas that influence the enhancement in IGC after passive ethanol exposure. The long-term goal of this project is to understand the genetic and neurobiological processes underlying the excessive drinking that contributes to alcoholism in humans. By improving our understanding of these processes, we can identify more effective treatment and prevention strategies.