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（触发物）能够 持续激发寻求毒品的行为，尽管会产生负面后果。当药物与 在药物和线索之间形成强烈的条件记忆。通常情况下，一旦这些线索不 如果你不再预测药物奖励，这种条件记忆就会被消退记忆所压倒。 灭绝记忆回忆（EMR）描述了行为表达这种灭绝记忆的能力。EMR缺陷 可能是OUD患者病理性药物寻求（复发）的基础。重要的是，一个大脑区域 在这个过程的每一个步骤（条件反射，消退和EMR）是基底外侧杏仁核（BLA）。OUD也是 其特点是明显的性别差异，女性特别容易受到奖励的影响， 对阿片类药物相关线索的反应更强烈。不幸的是，在许多先前的研究中， 对OUD的研究削弱了我们描述其背后机制的能力，从而削弱了我们解决这些问题的能力。 差距。为了解决这一知识缺口，我们进行了初步研究，以调查雌二醇的作用， (E2)在雄性和雌性啮齿动物中BLA中的海洛因EMR信号。在我们的第一项研究中，我们发现， E2的合成在BLA在线索灭绝训练损害EMR在两种性别。在随访中，我们发现， 拮抗BLA中的雌激素受体（ER）亚型导致对海洛因EMR的性别特异性影响。简言之， 接受ERβ拮抗剂的女性相对于所有其他测试组具有严重的EMR缺陷。在 一致，ERβ激动剂仅在雌性中增强EMR。这个提案的目的是评估性别- BLA中ERβ信号传导对海洛因EMR的特定影响。我们假设ERβ的调节 灭绝期间BLA中的信号传导将通过改变神经元功能来改变女性的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该假设。我们建议在男性中使用药理学和遗传学方法 和雌性动物，以确定BLA活性和信号传导的变化， (Aim（2）提示消退过程中ERβ的调节。根据分析，我们预期负性ERβ调节 拮抗剂或shRNA（Aim 1）可使海洛因EMR受损，降低ERβ+神经元活性， 可塑性相关的mRNA表达。相比之下，激动剂或受体拮抗剂对ERβ的正向调节作用， 过度表达（Aim 2）将对女性的这些指标产生相反的影响。拟议的研究可 更好地描述海洛因奖励处理和OUD的性别差异，允许更多的指导，性别- 具体的干预措施，以成功地预防和治疗这种疾病。这个奖学金将支持我的培训， 卡梅拉·瑞切尔和克里斯托弗·科万博士的指导如本建议书所述，我将接受培训 在（一）众多的技术和非技术科学技能，（二）调查性作为一个主要的生物 变量，以及（iii）考虑心理健康的生物和社会决定因素。