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

项目概要/摘要 药物滥用障碍 (SUD) 倾向的性别差异已得到证实，但 确定其机制基础的研究仍然很少。近年来，女性人数 SUD 明显增加，使用兴奋剂的少女人数已超过 男孩们。鉴于女性对滥用药物更敏感，发展 SUD 更快，发现更困难 一旦上瘾就戒掉，遭受更严重的戒断症状，并且在戒断之前表现出更短的时间 吸毒行为的人口变化代表了一场公共卫生危机。成瘾是一种 医疗、社会和经济负担，治疗选择很少，而且没有针对性别的治疗选择。因此，它是 了解成瘾的病理生理学以及如何最好地控制男性和女性的成瘾方法至关重要。在 在我的职业生涯中，我将建立一个独立的研究计划，调查并阐明细胞、分子 以及药物成瘾性别差异的具体机制。该提案将调查以下角色的作用： 内侧杏仁核（meAMY）是一个已知的性别二态性区域，在调节可卡因的性别差异中 自我管理（SA）。这个独立之路奖将为我提供一个继续发展的机会 大脑性别分化和细胞/分子神经科学方面的专业知识，同时 发展我在行为药理学和体内成像以及电路活动操纵方面的培训。在 在该奖项的指导（K99）部分中，我将重点关注 meAMY 活动中的性别差异以及 它通过对腹侧被盖区（VTA）的性别特异性输入来调节奖励。在师徒的指导下 博士。 Eric Nestler 和 Veronica Alvarez，我将研究 meAMY 细胞活动的暂时性 使用光纤光度法测量体内 Ca2 通量，与性别二态性 SA 行为相关。这个 尖端而强大的技术可以在采集过程中实时探测meAMY细胞活动 可卡因 SA，一种性别二态性行为。在保罗·肯尼博士的额外指导下，我将学习 通过化学遗传学抑制性别特异性来影响 meAMY 与 VTA 连接的性别差异功能 meAMY – 男性的 VTA 预测可逆转/减少 SA 获取中的性别差异。这些实验将 准备好我从功能上质疑 meAMY 作为奖励性别差异中介的作用 该奖项 R00 部分的整个中脑边缘多巴胺通路。我的独立实验室将 研究伏隔核 (NAc) 谷氨酸能输入调节中的 MEAMY 性别差异 并描述这些输入在性别二态性药物寻求行为中的作用。在 总之，独立之路奖中提出的研究将揭示独立的和潜在的 成瘾和药物滥用性别差异背后的相互作用的细胞和环路机制。更多 总的来说，该奖项提供的额外培训将使我做好启动独立研究计划的准备 在药物滥用的转化模型中评估从分子到电路的奖励的性别差异。

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.