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中推断出改善人类治疗的结果。从动物实验室到临床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差异。在药物滥用的动物模型中，操纵发生在初始暴露后相对较短的时间内;而在人类中，干预和复发可能发生在初始药物暴露后很长一段时间。研究药物滥用的一个流行范式是条件性位置偏好（CPP），其中药物与特定背景配对，随后通过评估动物对药物配对背景的偏好来评估与药物相关的动机。这种模式是有用的研究关联学习的基础灭绝（减少响应重复CS介绍）的药物诱导的协会。许多研究已经证实，情境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。一般来说，这表明最近的上下文记忆（1-7天）依赖于不同的基底提取比远程记忆（>28天）。这可能表明支持这些记忆消退的基质也不同。人们对与滥用药物有关的近期记忆和遥远记忆之间的差异知之甚少。拟议的研究将确定最近（新）的药物背景协会的记忆是否由不同的基板比远程（旧）的记忆支持。通过增加我们对最近和遥远的药物关联之间差异的理解，这项研究具有明确的翻译意义，因为药物关联的灭绝可能依赖于最近和遥远时间点不同的神经和表观遗传机制。因此，目标1将调查区域表观遗传修饰（组蛋白乙酰化）和基因表达后，最近或远程可卡因诱导的CPP灭绝，以确定是否在不同的时间点灭绝的结果在不同的基因表达模式。而Aim 2将使用HDAC和HAT抑制剂输注来检查海马内的不同表观遗传机制是否支持最近和远程CPP的消退。这些目标将确定最近和遥远的CPP灭绝之间是否存在表观遗传差异。缩略语：CPP：条件性位置偏爱; DH：你好背侧海马;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.