Making and breaking opioid memories to prevent relapse

建立和打破阿片类药物记忆以防止复发

基本信息

批准号：
10629259
负责人：
Erin Calipari
金额：
$ 47.55万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-05-31
项目状态：
未结题

项目摘要

Project Summary Repeated drug exposure produces widespread cellular alterations that can manifest in maladaptive behaviors and addiction. These behavioral alterations can be debilitating, and the pathology of addiction is often a life-long affliction. Indeed, even after years of abstinence, relapse can be precipitated by exposure to drug-associated cues. This is a ubiquitous property of drug addiction, and is present across drug class, yet we lack a clear understanding of how these changes can be so long lasting. Dysregulation of many classes of proteins have been implicated in cue-evoked relapse, yet the propensity to relapse persists well past the half-life of these proteins, suggesting that upstream epigenetic changes are permissive to the transcriptional landscape that produces these behavioral aberrations. Understanding the epigenetic alterations that ultimately produce these cellular changes will great expand the number of targets available for potential therapeutic interventions. To approach understanding the epigenetic mechanisms that underlie cue-induced relapse, we must identify the cells that are activated to drive seeking behavior. Our preliminary data show that in any given brain region, only a small percentage of cells are activated to a given stimulus – this group of activated neurons is termed a neural ensemble. Thus, the next frontier of understanding the brain will be defining exactly which cells are activated, when they are activated, and why. Here we combine techniques that allow us to record, manipulate, and sequence neural ensembles during opioid self-administration and subsequent cue-triggered drug seeking to determine how transcriptional activity within each neuronal population dictates which cells are activated. By combining in vivo cellular resolution calcium imaging during cue-induced seeking followed by single cell sequencing - in the same animals - we will define the transcriptional networks that control the neural activity patterns that drive drug seeking. Next, using epigenetic approaches and CRISPR/dCas9 fusion constructs, we will define and manipulate the epigenetic landscape at activity-responsive genes selectively in neurons that are activated by drug-associated cues. This proposal will allow us to define the precise neural ensembles that guide drug seeking and how transcriptional networks within these neurons control the neural activity profiles that guide behavior. By defining these mechanisms, this award will allow research that pushes the boundaries of how we approach understanding information encoding in the brain and expand our understanding of how we can manipulate these processes to reduce relapse across drug classes.

项目概要反复接触药物会产生广泛的细胞改变，从而表现为适应不良行为这些行为改变可能会使人衰弱，而且成瘾的病理往往是终生的。事实上，即使在戒断多年之后，接触与药物相关的药物也可能导致复发。这是药物成瘾的普遍特征，并且存在于各种药物类别中，但我们缺乏明确的线索。了解这些变化如何能够如此持久地影响许多类别的蛋白质。与提示诱发的复发有关，但复发的倾向在这些药物的半衰期之后仍然存在蛋白质，表明上游表观遗传变化允许转录景观了解最终产生这些行为异常的表观遗传改变。细胞变化将极大地增加可用于潜在治疗干预的靶标数量。为了了解线索诱导复发的表观遗传机制，我们必须确定我们的初步数据表明，在任何特定的大脑区域中，只有被激活以驱动寻找行为的细胞。一小部分细胞对给定的刺激被激活——这组激活的神经元被称为神经元因此，理解大脑的下一个前沿将是准确定义哪些细胞被激活，它们何时被激活，以及为什么。在这里，我们结合了一些技术，使我们能够记录、操纵和执行。在阿片类药物自我给药和随后的线索触发药物寻求过程中对神经系统进行排序确定每个神经群内的转录活动如何决定哪些细胞被激活。在线索诱导寻找过程中结合体内细胞分辨率钙成像，然后进行单细胞测序 - 在相同的动物中 - 我们将定义控制神经活动的转录网络接下来，我们使用表观遗传学方法和 CRISPR/dCas9 融合结构。将选择性地定义和操纵神经元中活动响应基因的表观遗传景观由药物相关线索激活的这一提议将使我们能够定义指导的精确神经系统。药物寻找以及这些神经元内的转录网络如何控制指导的神经活动概况通过定义这些机制，该奖项将允许研究突破我们的行为界限。方法了解大脑中的信息编码并扩展我们对如何能够进行编码的理解操纵这些过程以减少不同药物类别的复发。