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出改善人类治疗的发现。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的时间间隔不同。在药物滥用的动物模型中，操作在初次接触后相对较快地发生；然而，在人类中，干预和复发可能发生在最初的药物暴露后很长时间。研究药物滥用的一个流行范式是条件位置偏好（CPP），其中药物与特定情境配对，然后通过评估动物对药物配对情境的偏好来评估药物相关动机。这种模式对于研究药物诱导的关联消失（在重复CS呈现时反应减少）背后的联想学习是有用的。许多研究已经证实，情境学习在训练后的短时间内依赖海马体，但随后记忆巩固成为海马体独立。总的来说，这表明近期情境记忆（1-7天）与远程记忆（1- 28天）依赖于不同的提取基质。这可能表明，支持这些记忆消失的基质也不同。对于与药物滥用有关的近期记忆和远程记忆之间的差异，我们所知甚少。拟议的研究将确定最近（新）的药物上下文关联记忆是否由不同的底物支持，而不是由远（旧）记忆支持。通过增加我们对近期和远程药物关联之间差异的理解，该研究具有明确的翻译意义，因为药物关联的消失可能依赖于近期和远程时间点不同的神经和表观遗传机制。因此，Aim 1将研究区域表观遗传修饰（组蛋白乙酰化）和近期或远程可卡因诱导的CPP灭绝后的基因表达，以确定不同时间点的灭绝是否会导致不同的基因表达模式。然而，Aim 2将使用输注HDAC和HAT抑制剂来检查海马体内的不同表观遗传机制是否支持近期和远程CPP的灭绝。这些目标将确定近期和远程CPP灭绝之间是否存在表观遗传差异。缩写：CPP：有条件的地方偏好；DH：海马背侧；丁酸钠；组蛋白去乙酰化酶；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.