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

• 批准号: 10678227
• 负责人: Jordan Scott Carter
• 金额: $ 4.51万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678227
• 关键词: Abstinence; Address; Agonist; Agreement; Amygdaloid structure; Behavioral; Biological; Brain; Brain region; Cannulas; Chronic Disease; Cues; Data; Disease; Disparity; Down-Regulation; Economic Burden; Epidemic; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Evaluation; Exclusion; Extinction; FOS gene; Fellowship; Female; Fright; Goals; Government; Heroin; Impairment; Infusion procedures; Intervention; Investigation; Knowledge; Measures; Memory; Mental Health; Mentorship; Messenger RNA; Molecular; Neurons; Opioid; Overdose; Pathologic; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Prevalence; Process; Property; Protocols documentation; Rattus; Regulation; Relapse; Research; Resistance; Rewards; Risk; Rodent; Role; Self Administration; Sensory; Sex Differences; Signal Transduction; Substance Use Disorder; Synaptic plasticity; Testing; Therapeutic; Tissues; Training; Treatment outcome; Validation; Visual; addiction; antagonist; career; cell type; conditioning; cost; drug reward; drug seeking behavior; expression vector; follow-up; genetic approach; mRNA Expression; male; memory recall; neurosteroids; opioid use; opioid use disorder; overexpression; pharmacologic; prescription opioid misuse; prevent; receptor; research study; response; reward processing; sex; skills; small hairpin RNA; social determinants

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，其特征是药物相关线索（触发因素）能够 尽管毒品与毒品有关，但仍会持续地激发寻求毒品的行为。 通常，一旦这些线索消失，药物和线索之间就会形成强烈的条件记忆。 如果预测药物奖励的时间更长，这种条件记忆就会被灭绝记忆所压倒。 消退记忆回忆 (EMR) 描述了以行为方式表达这种消退记忆缺陷的能力。 可能是 OUD 患者病理性药物寻求（复发）的根源，重要的是，涉及的大脑区域。 在这个过程的每一步（调节、消退和 EMR）中，基底外侧杏仁核 (BLA) 也发挥着作用。 其特点是明显的性别差异，女性特别容易受到奖励效应的影响 不幸的是，在许多先前的研究中缺乏女性。 对 OUD 的研究削弱了我们描述背后机制并解决这些机制的能力 为了解决这一知识差距，我们进行了初步研究来调查雌二醇的作用。 (E2) 雄性和雌性啮齿类动物 BLA 中海洛因 EMR 的信号传导 在我们的第一项研究中，我们发现这种阻断作用。 在提示性消退训练期间，BLA 中的 E2 合成会损害两性的 EMR。 拮抗 BLA 中的雌激素受体 (ER) 亚型会对海洛因 EMR 产生性别特异性影响。 与所有其他测试组相比，接受 ERβ 拮抗剂的女性存在严重的 EMR 缺陷。 一致认为，ERβ 激动剂仅增强女性的 EMR。该提案的目标是评估性别。 BLA 中 ERβ 信号传导对海洛因 EMR 的具体影响 我们努力解决 ERβ 的调节问题。 灭绝期间 BLA 中的信号传导将通过改变神经功能来改变雌性的 EMR 可塑性相关的 mRNA 表达，这是由 BLA 中性别特异性 ERβ 表达驱动的效应。 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理学和遗传学方法。 和女性识别 BLA 活性和信号转导在阴性（目标 1）或阳性后的变化 （目标 2）提示消退期间 ERβ 的调节 经过分析，我们预计 ERβ 会出现负调节。 拮抗剂或 shRNA（目标 1）会损害海洛因 EMR，降低 ERβ+ 神经元活性，并减少 相比之下，雌性中可塑性相关的 mRNA 表达通过激动剂或 过度表达（目标 2）将对女性的这些措施产生相反的影响。 更好地描述海洛因奖励处理和 OUD 背后的性别差异，从而提供更多指导、性别差异 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。 正如本提案所述，我将在 Carmela Reichel 博士和 Christopher Cowan 博士的指导下获得培训。 (i) 众多的技术和非技术科学技能，(ii) 对性别作为主要生物的研究 变量，以及 (iii) 考虑心理健康的生物和社会决定因素。