Neural substrates of recent and remote cocaine memories

最近和遥远的可卡因记忆的神经基质

基本信息

批准号：
8253308
负责人：
Jon D Raybuck
金额：
$ 5.22万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8253308
关键词：
Abbreviations Acetylation Affect Amygdaloid structure Animal Model Animals Behavioral Behavioral Paradigm Brain region Brain-Derived Neurotrophic Factor Clinic Cocaine Cues Data Dorsal Drug Exposure Drug abuse Drug usage Epigenetic Process Event Exposure to Extinction (Psychology)Fright Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Human Immunohistochemistry Infusion procedures Intervention Laboratory Finding Learning Literature Medial Memory Modeling Modification Molecular Motivation Neurons Operative Surgical Procedures Pharmaceutical Preparations Prefrontal Cortex Process Relapse Research Retrieval Role Self Administration Sodium Butyrate Substance abuse problem System Time Training Translations Variant Work chromatin modification classical conditioning conditioned fear conditioning craving drug addiction pharmacotherapy drug craving drug of abuse drug testing garcinol histone acetyltransferase histone modification improved inhibitor/antagonist learning extinction neuromechanism novel preference relating to nervous system substance abuse treatment

项目摘要

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.

药物滥用动物模型研究的长期目标是推断实验室的研究结果以改善人类治疗。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，在初次接触后相对不久就会进行操作；而在人类中，干预和复发可能会在初次接触药物后很长时间内发生。研究药物滥用的一个流行范例是条件性位置偏好（CPP），其中将药物与特定环境配对，然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。这种范式对于研究药物引起的关联消退（重复 CS 呈现的反应减少）基础的关联学习很有用。许多研究已经证实，情境学习在训练后的短时间内会依赖于海马体，但随后记忆会巩固而变得独立于海马体。一般来说，这表明最近的情境记忆（1-7 天前）与远程记忆（>28 天前）相比，依赖于不同的检索基质。这可能表明支持这些记忆消失的基质也不同。对于与滥用药物相关的近期记忆和远期记忆之间的差异，人们知之甚少。拟议的研究将确定药物背景关联的近期（新）记忆是否由与远期（旧）记忆不同的基质支持。通过增加我们对近期和远期药物关联之间差异的理解，这项研究具有明确的转化意义，因为药物关联的消失可能依赖于近期和远期时间点不同的神经和表观遗传机制。因此，目标 1 将研究近期或远期可卡因诱导的 CPP 消退后的区域表观遗传修饰（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。同时，目标 2 将使用输注 HDAC 和 HAT 抑制剂来检查海马内不同的表观遗传机制是否支持近期和远期 CPP 的灭绝。这些目标将确定近期和远期 CPP 灭绝之间是否存在表观遗传差异。缩写：CPP：条件性位置偏好； DH：背侧海马； NaBut 丁酸钠； HDAC：组蛋白脱乙酰酶； HAT：组蛋白乙酰转移酶。