A novel role for the medial amygdala in the modulation of sex differences in cocaine reward

内侧杏仁核在调节可卡因奖励性别差异中的新作用

• 批准号: 10229614
• 负责人: Deena M. Walker
• 金额: $ 24.9万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229614
• 关键词: Abstinence; Adult; Amygdaloid structure; Award; Behavior; Brain; Cells; Cocaine; Consumption; Data; Development; Disease; Dopamine; Drug Addiction; Drug abuse; Drug usage; Economic Burden; Exhibits; Female; Female Adolescents; Fiber; Functional disorder; Gene Activation; Glutamates; Goals; Gonadal Steroid Hormones; Health Expenditures; Hippocampus (Brain); Immediate-Early Genes; Intervention; Knowledge; Laboratories; Maintenance; Measures; Medial; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Molecular; Monitor; Motivation; Neuroendocrinology; Neurons; Neurosciences; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Phase; Photometry; Population; Prefrontal Cortex; Public Health; Regulation; Relapse; Research; Research Personnel; Research Proposals; Rewards; Role; Self Administration; Sex Differences; Sex Differentiation; Stimulus; Substance Use Disorder; Sum; Techniques; Testing; Time; Training; Ventral Tegmental Area; Veronica; Volition; Weight; Withdrawal Symptom; Woman; addiction; behavioral pharmacology; boys; career; cocaine self-administration; drug of abuse; drug seeking behavior; experimental study; illicit drug use; in vivo; in vivo imaging; mRNA Expression; male; men; novel; programs; protein expression; response; reward circuitry; sex; sexual dimorphism; sexual role; skills; social; stimulant use; therapeutically effective; translational model

PROJECT SUMMARY/ABSTRACT Sex differences in the propensity to develop substance use disorders (SUD) are well established, but research to determine the mechanistic underpinnings remains sparse. In recent years, the number of women with SUD has markedly increased and the number of adolescent girls using stimulants has exceeded that of boys. Given that females are more sensitive to drugs of abuse, develop SUD more quickly, find it more difficult to quit once addicted, suffer greater withdrawal symptoms and exhibit shorter times of abstinence before relapse, this demographic shift in drug taking behaviors represents a public health crisis. Addiction is a medical, social and economic burden with few treatment options and none that are sex-specific. Therefore, it is imperative to understand the pathophysiology of addiction and how best to manage it, in men and women. In my career, I will build an independent research program that investigates and clarifies the cellular, molecular and circuit specific mechanisms of sex differences in drug addiction. This proposal will investigate the role of the medial amygdala (meAMY), a known sexually dimorphic region, in modulating sex differences in cocaine self-administration (SA). This Pathway to Independence Award will provide the opportunity to build on my expertise in sexual differentiation of the brain and cellular/molecular neuroscience while simultaneously developing my training in behavioral pharmacology and in vivo imaging and manipulation of circuit activity. In the mentored (K99) portion of this award, I will focus on characterizing sex differences in meAMY activity and its modulation of reward through sex-specific inputs to the ventral tegmental area (VTA). Under the mentorship of Drs. Eric Nestler and Veronica Alvarez, I will investigate how meAMY cellular activity is temporally associated with sexually dimorphic SA behaviors using fiber photometry to measure in vivo Ca2+ flux. This cutting-edge and powerful technique can probe meAMY cellular activity in a real-time during acquisition of cocaine SA, a sexually dimorphic behavior. With additional mentorship from Dr. Paul Kenny, I will study the functionality of sex differences in connectivity of the meAMY to VTA by chemogenetically inhibiting sex-specific meAMY – VTA projections in males to reverse/reduce sex difference in SA acquisition. These experiments will prepare me to functionally interrogate the role of the meAMY as a mediator of sex differences in reward throughout mesolimbic dopamine pathways in the R00 portion of this award. My independent laboratory will investigate meAMY sex differences in modulation of glutamatergic inputs to the nucleus accumbens (NAc) during operant SA and characterize the role of these inputs in sexually dimorphic drug-seeking behaviors. In sum, the research proposed in this Pathway to Independence Award will reveal both separate and potentially interactive cellular and circuit-wide mechanisms underlying sex differences in addiction and drug abuse. More broadly, the added training afforded by this award will prepare me to launch an independent research program evaluating sex differences in reward, from molecules to circuitry, in a translational model of drug abuse.

项目总结/摘要 发展物质使用障碍（SUD）倾向的性别差异已得到充分证实，但 确定机制基础的研究仍然很少。近年来，妇女人数 使用兴奋剂的少女人数已超过100万人， 小伙子们鉴于女性对滥用药物更敏感，SUD发展得更快， 一旦上瘾就戒掉，戒断症状更严重，戒断时间更短， 复发，这种吸毒行为的人口变化代表了一场公共卫生危机。成瘾是一 医疗、社会和经济负担，治疗选择很少，而且没有针对性别的选择。因此有 必须了解成瘾的病理生理学，以及如何最好地管理它，在男性和女性。在 在我的职业生涯中，我将建立一个独立的研究计划，调查和澄清细胞，分子， 以及药物成瘾性别差异的电路特异性机制。本提案将研究以下方面的作用： 内侧杏仁核（meAMY），一个已知的性二态区域，在调节可卡因的性别差异 自我管理（SA）。这个独立之路奖将提供一个机会，以建立在我的 专业知识的性别分化的大脑和细胞/分子神经科学，同时 发展我在行为药理学和体内成像和电路活动操纵方面的训练。在 在这个奖项的指导（K99）部分，我将专注于描述meAMY活动中的性别差异， 通过对腹侧被盖区（VTA）的性别特异性输入来调节奖励。在指导下 Eric Nestler和Veronica Alvarez博士的研究，我将研究细胞活动在时间上是如何变化的。 与性二态SA行为相关，使用纤维光度法测量体内Ca 2+通量。这 尖端和强大的技术可以探测meAMY细胞活动在采集过程中实时 可卡因SA，一种性二态行为。在保罗·肯尼博士的指导下，我将学习 通过化学遗传学抑制性别特异性 meAMY-男性VTA投射逆转/减少SA获得的性别差异。这些实验将 准备我功能性地询问的作用，meAMY作为中介的性别差异的奖励 在这个奖项的R00部分的中脑边缘多巴胺通路。我的独立实验室将 研究丘脑腹外侧核（NAc）神经元能输入调节的性别差异 在操作性SA和特征的作用，这些输入性二态性药物寻求行为。在 总之，这项独立之路奖中提出的研究将揭示独立和潜在的 交互式细胞和电路机制的性别差异成瘾和药物滥用。更 总的来说，这个奖项所提供的额外培训将使我为启动一个独立的研究项目做好准备 评估奖励的性别差异，从分子到电路，在药物滥用的翻译模型。