Establishing sex-specific mechanisms for estrogen receptor beta in heroin extinction memory recall

建立海洛因灭绝记忆回忆中雌激素受体β的性别特异性机制

基本信息

项目摘要

Opioid use disorder (OUD) is a chronic disorder characterized by the ability of drug-associated cues (triggers) to persistently motivate drug-seeking behaviors, despite negative consequences. When drugs are associated with cues, a strong conditioned memory is formed between the drug and the cues. Normally, once these cues no longer predict a drug reward, this conditioned memory would be overpowered by an extinction memory. Extinction memory recall (EMR) describes the ability to behaviorally express this extinction memory. EMR deficits may underly the pathological drug seeking (relapse) seen in those with OUD. Importantly, a brain region involved in each step of this process (conditioning, extinction and EMR) is the basolateral amygdala (BLA). OUD is also characterized by distinct sex differences, with females being particularly susceptible to the rewarding effects of opioids and more reactive to opioid-associated cues. Unfortunately, the lack of females in many prior research studies on OUD has impaired our ability to describe the mechanisms behind, and thereby address, these disparities. To resolve this knowledge gap, we conducted preliminary studies to investigate the role of estradiol (E2) signaling in the BLA on heroin EMR in male and females rodents. In our first study, we found that blocking E2 synthesis in the BLA during cued extinction training impairs EMR in both sexes. On follow-up, we found that antagonizing estrogen receptor (ER) subtypes in the BLA led to sex-specific impacts on heroin EMR. Briefly, females who received an ERβ antagonist had a profound EMR deficit relative to all other groups tested. In agreement, ERβ agonism enhanced EMR in females only. The goal of this proposal is to evaluate the sex- specific impacts of ERβ signaling in the BLA on heroin EMR. We hypothesize that modulation of ERβ signaling in the BLA during extinction will alter EMR in females by changing neuronal function and plasticity-associated mRNA expression, an effect driven by sex-specific ERβ expression in the BLA. We will evaluate this hypothesis across 2 Aims. We propose to use pharmacologic and genetic approaches in males and females to identify alterations in BLA activity and signaling following negative (Aim 1) or positive (Aim 2) modulation of ERβ during cued extinction. Upon analysis, we expect that negative ERβ modulation by antagonist or shRNA (Aim 1) will impair heroin EMR, decrease ERβ+ neuronal activity, and decrease plasticity-associated mRNA expression in females. Contrastingly, positive modulation of ERβ by agonist or overexpression (Aim 2) will have opposite impacts on these measures in females. The proposed studies may better describe sex differences underlying heroin reward processing and OUD, allowing for more guided, sex- specific interventions to successfully prevent and treat this disorder. This fellowship will support my training under the mentorship of Drs. Carmela Reichel and Christopher Cowan. As outlined in this proposal, I will gain training in (i) numerous technical and non-technical scientific skills, (ii) investigation of sex as a primary biological variable, and (iii) consideration of biological and social determinants of mental health.
阿片类药物使用障碍(OUD)是一种慢性疾病,其特征是与药物相关线索(触发器)的能力 持续动机的寻求毒品行为,使命负面后果。当药物与 提示,在药物和提示之间形成了强烈的条件记忆。通常,一旦这些提示不 更长的时间预测药物奖励,这种条件记忆将被扩展记忆所压倒。 消光内存回忆(EMR)描述了行为表达此扩展存储器的能力。 EMR定义 可以在患有OUD的患者中发现(复发)的病理药物。重要的是,涉及的大脑区域 在此过程的每个步骤中(条件,扩展和EMR)是基础杏仁核(BLA)。 Oud也是 以明显的性别差异为特征,女性特别容易受到奖励的影响 卵虫类药物和对卵巢相关的提示更具反应性。不幸的是,在许多先前的研究中缺乏女性 OUD的研究损害了我们描述背后机制的能力,从而解决了这些机制 差异。为了解决这一知识差距,我们进行了初步研究以研究雌二醇的作用 (E2)在男性和雌性啮齿动物中对海洛因EMR的BLA发出信号。在我们的第一个研究中,我们发现阻止 提示扩展训练期间BLA中的E2合成会损害两性的EMR。在后续行动中,我们发现 BLA中拮抗雌激素受体(ER)亚型导致性别特异性对海洛因EMR的影响。简要地, 接受ERβ拮抗剂的女性相对于所有其他测试的组具有深远的EMR缺陷。在 一致,ERβ激动剂仅增强了女性的EMR。该提案的目的是评估性别 - ERβ信号在BLA中对海洛因EMR的特定影响。我们假设ERβ的调节 扩展过程中BLA中的信号传导将通过改变神经元功能和 塑性相关的mRNA表达,这是由性别特异性ERβ表达在BLA中驱动的效果。我们 将在两个目标中评估这一假设。我们建议在男性中使用药物和遗传方法 和女性确定BLA活性和信号传导的变化(AIM 1)或阳性 (AIM 2)在提示延伸过程中对ERβ的调制。通过分析,我们期望负ERβ调制 通过拮抗剂或shRNA(AIM 1)会损害海洛因EMR,降低ERβ+神经元活性并减少 女性中与塑性相关的mRNA表达。相反,激动剂或 过表达(AIM 2)将对女性的这些措施产生相反的影响。拟议的研究可能 更好地描述海洛因奖励加工和OUD的性别差异,使得更加指导性,性别 - 成功预防和治疗这种疾病的具体干预措施。该奖学金将支持我的培训 博士的心态。 Carmela Reichel和Christopher Cowan。如本提案中概述的那样,我将获得培训 在(i)众多技术和非技术科学技能中,(ii)对性作为主要生物学的研究 可变,以及(iii)考虑生物学和社会对心理健康的决定。

项目成果

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