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 伴随着高阿片类药物相关死亡率。应对这场危机的有效战略迫在眉睫 需要，并在他们上瘾之前识别高危人群将是对抗这种日益增长的 流行病。尽管遗传因素在成瘾易感性中起到了一定作用，但它们本身并不能解释成瘾率的急剧上升。 阿片类药物成瘾发生率近年来呈上升趋势。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)，如社会经济地位低， 创伤或混乱的环境与终生情感问题有关，这些问题表明 大脑的奖励回路，包括冒险行为和吸毒。然而，神经生物学机制 目前还不清楚这种情况是通过什么方式发生的。我的项目将考察ELA对寻求毒品行为和奖励的影响 大鼠的电路功能，追求一种机械性的理解，这将为新的翻译干预提供信息 或阿片成瘾的预防策略。为此，我将实现一个强大的、自然主义的ELA模型 在老鼠身上。在这个模型中，贫困是通过向产后提供有限的床上用品和筑巢材料来模拟的 妈的。这引发了类似于人类经历ELA的产妇护理的混乱模式，并且 由此产生的慢性压力会导致奖赏回路的深刻变化。要理解行为暗示 在这些被破坏的电路中，我将使用现有的方法来模拟阿片成瘾，包括自我 管理、灭绝抵抗和恢复，以及最近开发的与翻译相关的 寻找阿片类药物的行为经济学模型，也可以用来量化人类的成瘾严重程度。 基于我最近发表的发现，ELA饲养的雌性大鼠非常容易患上 发展类阿片成瘾行为，我将确定ELA如何与生物性相互作用来改变 对阿片类药物成瘾的易感性，可能具有性别特异性。为了定义神经生物学机制 我将测试ELA是否改变了海洛因诱导的活动 伏隔核(NAC)，以及该区域恢复正常活动是否逆转增强的阿片类药物- 寻找，从而确定ELA形成奖励回路以增加阿片类药物的因果机制 上瘾的脆弱性。这些研究代表了一个独特的机会来理解发展的作用 阿片成瘾的危险因素，并将阐明这些危险因素背后的神经生物学机制 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.