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

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的线索(触发物)能够 不顾负面后果，坚持不懈地激发吸毒行为。当药物与 线索，在药物和线索之间形成了强大的条件记忆。通常情况下，一旦这些提示没有 对药物奖励的预测时间越长，这种条件性记忆就会被消亡记忆所压倒。 消亡记忆回忆(EMR)描述了从行为上表达这种消亡记忆的能力。电子病历赤字 可能是OUD患者的病理性药物寻找(复发)。重要的是，大脑中的一个区域 在这个过程的每一步(条件反射、消退和EMR)都是杏仁基底外侧核(BLA)。OUD也是 以明显的性别差异为特征的，女性特别容易受到 阿片类药物，对阿片类药物相关线索的反应更强。不幸的是，在之前的许多研究中，缺乏女性 对OUD的研究削弱了我们描述背后机制的能力，从而解决了这些问题 差距。为了解决这一认识差距，我们进行了初步研究，以调查雌二醇的作用。 (2)雄性和雌性啮齿动物海洛因EMR的血乳酸中的信号。在我们的第一项研究中，我们发现阻断 提示消退训练期间血乳酸中的E2合成会损害男女的EMR。在后续的工作中，我们发现 拮抗BLA中的雌激素受体(ER)亚型导致了性别特异性的影响海洛因EMR。简单地说， 接受ERβ拮抗剂的女性与所有其他测试组相比，有严重的EMR缺陷。在……里面 一致认为，ERβ激动剂仅在女性中增强EMR。这项提案的目标是评估性别- 血中ER-β信号对海洛因EMR的特异性影响我们假设ERβ的调制 灭绝期间BLA中的信号将通过改变神经元功能和 可塑性相关基因的表达，这是一种由BLA中性别特异性ERβ表达驱动的效应。我们 将在两个目标上评估这一假设。我们建议在男性身上使用药理学和遗传学方法 和女性来识别BLA活性和信号在否定(目标1)或积极之后的变化 (目的2)线索消退时ERβ的调制。经过分析，我们预计负ERβ调制 使用拮抗剂或shRNA(Aim 1)将损害海洛因的EMR，降低ERβ+神经元的活性，并降低 女性可塑性相关基因的表达。相反，激动剂OR对ERβ的正向调节作用 过度表达(目标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背后的性别差异，允许更多的引导，性行为- 成功预防和治疗这种疾病的具体干预措施。这笔奖学金将支持我在以下领域的培训 Carmela Reichel博士和Christopher Cowan博士的指导。正如这项提议所概述的那样，我将接受培训 在(一)许多技术和非技术科学技能中，(二)将性作为主要的生物学 (3)考虑心理健康的生物和社会决定因素。

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.