Neural substrates of recent and remote cocaine memories

药物滥用动物模型研究的长期目标是从实验室推断结果，以改进人类的治疗方法。从动物实验室到临床的有效转化的一个主要限制是药物暴露和潜在治疗测试之间所经过的时间不同。在药物滥用的动物模型中，操纵发生在首次接触后相对较短的时间；而在人类中，干预和复发可能发生在首次接触药物后很长一段时间。研究药物滥用的一个流行范式是条件性位置偏好(CPP)，其中一种药物与特定的环境配对，随后通过评估动物对药物配对环境的偏好来评估与药物相关的动机。这一范式对研究药物诱导联想消失(重复CS呈现时反应减少)的联想学习很有用。许多研究已经证实，情景学习在训练后的短时间内依赖于海马体，但后来记忆巩固，成为海马体独立的。总体而言，这表明最近的情境记忆(1-7天大)依赖于不同于远程记忆(28天大的记忆)的提取底物。这可能表明，支持这些记忆消亡的底物也不同。值得注意的是，人们对与滥用药物有关的近期记忆和远程记忆之间的差异知之甚少。这项拟议的研究将确定药物背景关联的近期(新)记忆是否得到了与远程(旧)记忆不同的底物的支持。通过增加我们对近期和远程药物关联之间差异的理解，这项研究具有明确的翻译意义，因为药物关联的消亡可能依赖于最近和远程时间点不同的神经和表观遗传机制。因此，目标1将研究近期或远程可卡因诱导的CPP消退后的局部表观遗传修饰(组蛋白乙酰化)和基因表达，以确定不同时间点的消退是否会导致不同的基因表达模式。然而，AIM 2将使用注射HDAC和HAT抑制剂来检查海马体内不同的表观遗传机制是否支持最近和远程CPP的消退。这些目标将决定近期和远期CPP的灭绝之间是否存在表观遗传学差异。缩写：CPP：条件性位置偏爱；DH：背侧海马区；NaBut丁酸钠；HDAC：组蛋白脱乙酰酶；HAT：组蛋白乙酰转移酶。

The long-term goal of research with animal models of substance abuse is to extrapolate findings from the laboratory to improve human treatments. A major limitation in making effective translations from the animal lab to the clinic is the differnt time elapsed between drug exposure and testing of potential treatments. In animal models of substance abuse, manipulations occur relatively soon after initial exposure; whereas in humans, intervention and relapse can occur long after initial drug exposure. A popular paradigm in studying drug abuse is conditioned place preference (CPP), wherein a drug is paired with a specific context, and later drug-associated motivation is assessed by evaluating the animal's preference for the drug-paired context. This paradigm is useful for studying the associative learning that underlies extinction (reduced responding over repeated CS presentations) of drug-induced associations. Much research has established that contextual learning depends upon the hippocampus for a short time after training, but later the memory consolidates to become hippocampus independent. In general, this suggests that recent contextual memories (1-7 days old) depend on different substrates for retrieval than remote memories (>28 days old). This may suggest that substrates supporting extinction of these memories differ as well. Remarkably little is known about the differences between recent and remote memories that are associated with drugs of abuse. The proposed research will determine whether recent (new) memories for drug-context associations are supported by different substrates than remote (old) memories. By increasing our understanding of the differences between recent and remote drug associations, this research has clear translational implications, because extinction of drug-associations may rely on different neural and epigenetic mechanisms at recent and remote time points. Thus, Aim 1 will investigate regional epigenetic modification (histone acetylation) and gene expression following extinction of recent or remote cocaine-induced CPP, to determine if extinction at different time points results in different patterns of gene expression. While, Aim 2 will use infusion HDAC and HAT inhibitors to examine if different epigenetic mechanisms within the hippocampus support extinction of recent and remote CPP. These aims will determine if there are epigenetic differences between extinction of recent and remote CPP. Abbreviations: CPP: Conditioned place preference; DH: Dorsal hippocampus; NaBut Sodium Butyrate; HDAC: Histone Deacetylase; HAT: Histone Acetyltransferase.