Genomic Analysis of Avoidance Learning in Addiction

摘要： 成瘾是人类神经精神疾病中最易遗传的疾病之一，但人类基因 人类遗传学的极端复杂性以及纯粹的 上瘾过程的行为复杂性，人类可以在多个阶段表现出 成瘾易感性--例如，初次吸毒、吸毒升级、吸毒复发等。我们解决这些问题 通过研究异种系(HS)大鼠的缺点，这些大鼠具有非常好的特征 遗传特征，并使用行为模型来检查 成瘾行为的进展。我们的初步发现表明，尽管上瘾通常是 被认为是异常的奖赏学习，成瘾倾向上的许多个体差异实际上是由于 在回避学习上的差异。例如，除了众所周知的奖励性质外， 可卡因具有令人厌恶的影响，表现出比其奖励作用更大的个体差异，并且 可卡因寻求者的预测能力更强。此外，我们还发现老鼠在“惩罚”方面有很大的不同 抵抗力“，即不顾不利结果寻求奖励的倾向，这是定义之一 成瘾的特点。避免吸食可卡因和抵抗惩罚都是高度可遗传的 HS大鼠(H2分别为0.58和0.48)，两者都受旋转内侧核的严格调控 被盖核(RMTg)是中脑多巴胺能神经元的主要GABA能传入，起着关键作用。 在回避学习中的作用。在这些发现的基础上，我们试图确定基因差异 利用全基因组关联对这两种不同的成瘾易感性表型进行研究 筛选HS大鼠候选基因，并对其进行eQTL分析 在驱动这些行为的RMTg和传入电路中表达。该项目将确定 使用强大的行为测试的高度创新组合来候选与成瘾相关的基因， 丰富的神经回路知识，以及帕尔默实验室开创性的测序和分析 接近了。

Abstract: Addictions are among the most heritable of human neuropsychiatric disorders, but human genetic studies have been hampered by the extreme complexity of human genetics, as well as the sheer behavioral complexity of the addictive process, with multiple stages at which humans can exhibit addiction vulnerability – e.g. initial drug exposure, escalation, relapse, etc. We address these shortcomings by studying heterogeneous stock (HS) rats, which have extremely well characterized genetic profiles, and using behavioral models that examine multiple well-defined time periods in the progression of addictive behaviors. Our preliminary findings show that even though addiction is often viewed as aberrant reward learning, much individual variation in addiction propensity is actually due to differences in avoidance learning. For example, in addition to its well-known rewarding properties, cocaine has aversive effects that show greater individual variability than its rewarding effects, and are stronger predictors of cocaine-seeking. Furthermore, we found that rats differ greatly in “punishment resistance”, i.e. propensity to seek rewards despite adverse outcomes, which is one of the defining characteristics of addiction. Both cocaine avoidance and punishment resistance are highly heritable in HS rats (h2 = 0.58 and 0.48, respectively), and both are critically regulated by the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons that plays key roles in avoidance learning. Building on these findings, we seek to identify the genetic differences underlying these two distinct addiction vulnerability phenotypes using a genome-wide association screen (GWAS) to identify candidate genes in HS rats, followed by eQTL analysis on gene expression in the RMTg and afferent circuits that drive these behaviors. This project will identify candidate addiction-related genes using a highly innovative combination of powerful behavioral tests, extensive neural circuitry knowledge, and the Palmer lab's groundbreaking sequencing and analytical approaches.