Effects of Early Life Adversity on Opioid Addiction Vulnerability

项目摘要 在过去的二十年里，美国经历了阿片类药物使用障碍的日益流行 伴随着与阿片类药物有关的高死亡率。应对这一危机的有效战略迫切需要 需要，并确定在他们上瘾之前的风险个人将是至关重要的打击这种增长 疫情尽管遗传学在成瘾脆弱性中发挥了作用，但它们本身并不能解释成瘾率的急剧上升。 近年来，阿片类药物成瘾的发病率。因此，成功的预防战略还必须考虑到 环境风险因素。例如，在人类中，早期生活逆境（ELA），如低社会经济地位， 创伤，或混乱的环境，与终身的情感问题，表明功能障碍， 大脑的奖励回路，包括冒险行为和药物使用。然而，神经生物学机制 这种情况发生的原因是未知的。我的项目将研究ELA对吸毒行为和奖励的影响 电路功能的大鼠，在追求一个机械的理解，将通知新的翻译干预 或阿片类药物成瘾的预防策略。为此，我将实现一个强大的、自然主义的ELA模型 对大鼠在这个模型中，贫困是通过向产后妇女提供有限的床上用品和筑巢材料来模拟的。 大坝这引发了类似于人类经历ELA的混乱的孕产妇护理模式， 由此产生的慢性压力会引起奖赏回路的深刻变化。为了理解行为暗示 在这些被破坏的回路中，我将使用建立阿片类药物成瘾模型的方法，包括自我- 管理，灭绝抗性，恢复，以及最近开发的，预防性相关的 阿片类药物寻求的行为经济模型，也可用于量化人类成瘾的严重程度。 基于我最近发表的发现，ELA饲养的雌性大鼠非常容易受到 发展阿片类药物成瘾样行为，我将确定ELA如何与生物性别相互作用，以改变 对阿片类药物成瘾的脆弱性在一个潜在的性别特异性方式。为了明确神经生物学机制 这是ELA诱导的阿片类药物脆弱性的基础，我将测试ELA是否改变海洛因诱导的活动， 丘脑核（NAc），以及恢复该区域的正常活动是否会逆转阿片样物质的增加， 寻找，从而确定ELA塑造奖励循环以增加阿片类药物的因果机制 成瘾的脆弱性这些研究代表了一个独特的机会，以了解发展的作用， 阿片类药物成瘾的危险因素，并将阐明神经生物学机制，这些基础 漏洞

Project Summary Over the past twenty years, the United States has experienced a growing epidemic of opioid use disorder accompanied by high rates of opioid-related mortality. Effective strategies to combat this crisis are urgently needed, and identifying at-risk individuals before they become addicted will be critical for fighting this growing epidemic. Although genetics play a role in addiction vulnerability, they alone cannot account for the dramatic rise in opioid addiction incidence in recent years. Therefore, successful prevention strategies must also consider environmental risk factors. For example, in humans, early-life adversity (ELA), such as low socioeconomic status, trauma, or chaotic environment, is associated with life-long affective problems that indicate dysfunction of the brain’s reward circuitry, including risk-taking behaviors and drug use. However, the neurobiological mechanisms by which this occurs are unknown. My project will examine effects of ELA on drug-seeking behavior and reward circuit function in rats, in pursuit of a mechanistic understanding that will inform novel translational intervention or prevention strategies for opioid addiction. To this end, I will implement a powerful, naturalistic model of ELA in rats. In this model, poverty is simulated by providing limited bedding and nesting materials to a postpartum dam. This provokes chaotic patterns of maternal care that are analogous to humans experiencing ELA, and the resulting chronic stress induces profound changes in reward circuits. To understand the behavioral implications of these disrupted circuits, I will use established methods for modeling opioid addiction including self- administration, extinction resistance, and reinstatement, as well as a recently-developed, translationally-relevant behavioral economic model of opioid seeking that can also be used to quantify addiction severity in humans. Building upon my recently-published findings that ELA-reared female rats are remarkably vulnerable to developing opioid addiction-like behaviors, I will determine how ELA interacts with biologic sex to alter vulnerability to opioid addiction in a potentially sex-specific manner. To define the neurobiological mechanisms that underlie ELA-induced opioid vulnerability, I will test whether ELA alters heroin-induced activity within the nucleus accumbens (NAc), and whether restoring normal activity in this region reverses augmented opioid- seeking, thereby identifying a causal mechanism by which ELA shapes reward circuity to increase opioid addiction vulnerability. These studies represent a unique opportunity to understand the role of developmental risk factors in opioid addiction and will elucidate the neurobiological mechanisms that underlie these vulnerabilities.