Role of Class IIa HDAC Target Genes in Opioid and Cocaine Addiction

IIa 类 HDAC 靶基因在阿片类药物和可卡因成瘾中的作用

基本信息

批准号：
10401908
负责人：
Christopher W Cowan
金额：
$ 37.38万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401908
关键词：
Adult Animal Model Basic Science Behavior Behavioral Binding Biological Assay Brain Cell physiology Cells ChIP-seq Chromatin Structure Cocaine Cocaine Dependence Corpus striatum structure Cues DARPP Development Discrimination Discrimination Learning Drug Addiction Drug usage Electrophysiology (science)Enhancers Environment Enzymes Epigenetic Process Event Extinction (Psychology)Foundations Future Gene Expression Genes Glutamates Goals Grant HDAC4 gene HDAC5 gene Heroin Histone Deacetylase Immediate-Early Genes Individual Inhibitory Synapse Interneurons Intravenous Lead Learning Link Literature Measures Memory Molecular Molecular Genetics Mus NPAS4 gene Neurons Nucleus Accumbens Opiate Addiction Opioid Parvalbumins Pharmaceutical Preparations Play Population Process Psychological reinforcement Publishing Regulation Relapse Reporting Research Research Proposals Rewards Role Saline Self Administration Series Substance Use Disorder Synapses Synaptic Transmission Synaptic plasticity Tamoxifen Testing Training Virus addiction base cell type cocaine self-administration conditioned place preference conditioning cue reactivity density drug abstinence drug addict drug discrimination drug reward experimental study gain of function genetic approach in vivo insight learning extinction multidisciplinary new therapeutic target novel patch clamp psychostimulant response therapeutic development transcription factor

项目摘要

SPECIFIC AIMS External and internal cues associated with the drug use environment often develop into persistent and powerful triggers for relapse to drug seeking. Many studies have reported that epigenetic enzymes, like histone deacetylases (HDACs), that alter chromatin structure and influence gene expression play an important role in addiction-relevant behaviors in animal models. In the previous grant period, we showed that the class IIa HDACs, HDAC5, plays important roles in the regulation of multiple cocaine-induced behaviors, including drug related learning and memory. The HDAC5 target gene, Npas4, emerged as an important, novel transcription factor required in the adult NAc for cocaine conditioned place preference and operant drug discrimination learning in the mouse intravenous self-administration. Our preliminary findings indicate that NPAS4 is induced in DARPP-32-positive medium spiny neurons (MSNs) and parvalbumin-positive fast spiking interneurons (PV- FSIs), but the relevant population(s) in which NPAS4 regulates drug behaviors remains unknown. Our long-term goal is to understand the role and regulation of NPAS4 in the development and/or persistence of drug addiction-related behaviors. Our central hypothesis is that NPAS4 induction within one or more subpopulations of activated NAc neurons promotes glutamatergic synaptic plasticity events that underlie long-lasting drug context/cue learning and memory. We will employ a series of multi-disciplinary, hypothesis testing experiments and cutting-edge molecular genetic approaches that will interrogate the in vivo cell type- specific role and regulation of NPAS4 and NPAS4-expressing cells in the NAc for drug addiction-related learning and memory. We will test and refine our central hypothesis with the following specific aims: Specific Aim 1: Determine the cell-type specific roles for NPAS4 during acquisition and extinction of drug self-administration. In this aim, we will take a cell-type specific loss- and gain-of-function approaches to study the function of NPAS4 during operant discrimination and extinction learning in the mouse drug self- administration assay. Specific Aim 2: Determine whether NPAS4-positive NAc neurons define a functional “engram” population linking external cues to drug reward and seeking. Using our newly developed Npas4 enhancer-driven, tamoxifen-dependent cre virus, we will use a chemogenetic approach to manipulate the activity of the NPAS4-positive population and test its role in durg taking and seeking behaviors. Specific Aim 3: Determine the cellular function of NPAS4 in the NAc during drug SA. We will use cell- type specific loss- and gain-of-function strategies to evaluate the effects of NPAS4 on excitatory ad inhibitory synapse plasticity in mice self-administering cocaine or heroin.

具体目标与吸毒环境相关的外部和内部线索通常会发展为持久的和许多研究报告称，表观遗传酶（如组蛋白）是导致药物复发的强大诱因。脱乙酰酶 (HDAC) 可以改变染色质结构并影响基因表达，在在动物模型中与成瘾相关的行为在之前的资助期间，我们证明了 IIa 类。 HDACs，HDAC5，在调节多种可卡因诱导的行为中发挥着重要作用，包括药物 HDAC5 靶基因 Npas4 作为一种重要的新型转录出现。成人 NAc 中可卡因条件性位置偏好和操作性药物歧视所需的因素我们的初步研究结果表明 NPAS4 是被诱导的。在 DARPP-32 阳性中型多棘神经元 (MSN) 和小白蛋白阳性快速尖峰中间神经元 (PV- FSI），但 NPAS4 调节药物行为的相关人群仍然未知。我们的长期目标是了解 NPAS4 在开发和/或我们的中心假设是 NPAS4 在一个或多个内诱导。更多激活的 NAc 神经元亚群促进谷氨酸能突触可塑性事件我们将采用一系列多学科的假设来实现持久的药物背景/线索学习和记忆。测试实验和尖端分子遗传学方法将询问体内细胞类型 - NAc 中 NPAS4 和 NPAS4 表达细胞对药物成瘾相关的特定作用和调节我们将通过以下具体目标来测试和完善我们的中心假设：具体目标 1：确定 NPAS4 在获得和消退过程中的细胞类型特定作用为了实现这一目标，我们将采取细胞类型特异性功能丧失和获得的方法。研究 NPAS4 在小鼠药物自我操作辨别和消退学习过程中的功能给药测定。具体目标 2：确定 NPAS4 阳性 NAc 神经元是否定义了功能性“印迹” 使用我们新开发的 Npas4 将外部线索与药物奖励和寻求联系起来。增强子驱动的、他莫昔芬依赖的 cre 病毒，我们将使用化学遗传学方法来操纵 NPAS4 阳性人群的活动并测试其在药物服用和寻求行为中的作用。具体目标 3：确定药物 SA 期间 NAc 中 NPAS4 的细胞功能。类型特异性功能丧失和获得策略来评估 NPAS4 对兴奋性和抑制性的影响自我施用可卡因或海洛因的小鼠的突触可塑性。