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

项目摘要/摘要 发生物质使用障碍(SUD)的倾向上的性别差异是公认的，但 确定这种机制基础的研究仍然很少。近年来，女性的数量 患有SUD的人数明显增加，使用兴奋剂的青春期女孩数量已超过#年。 孩子们。考虑到女性对滥用药物更敏感，所以发展得更快，发现更难 一旦上瘾就戒烟，经历更严重的戒断症状，并表现出较短的戒断时间 旧病复发，吸毒行为的这种人口结构变化代表着公共健康危机。上瘾是一种 医疗、社会和经济负担，几乎没有治疗选择，而且没有针对性别的治疗选择。因此，它是 必须了解成瘾的病理生理学，以及如何最好地管理它，无论是男性还是女性。在……里面 我的职业生涯，我将建立一个独立的研究计划，调查和澄清细胞，分子 以及药物成瘾中性别差异的回路特异性机制。这项提案将调查 杏仁内侧核(MeAMY)，一个已知的性二型区域，在调节可卡因的性别差异中 自治(SA)。这个独立之路奖将提供一个机会，让我在我的基础上 在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、体内成像和电路活动操纵方面的培训。在……里面 在这个奖项的导师(K99)部分，我将专注于描述男性活动中的性别差异和 它通过对腹侧被盖区(VTA)的性别特异性输入来调节奖赏。在导师的指导下 对于埃里克·内斯特勒博士和维罗妮卡·阿尔瓦雷斯博士，我将研究细胞活动是如何在时间上 使用纤维光度法测量体内钙离子流量与性二型SA行为有关。这 尖端而强大的技术可以在收购过程中实时探测meamy细胞活动 可卡因SA，一种性二态行为。在保罗·肯尼博士的额外指导下，我将研究 性别差异通过化学遗传学抑制性别特异性在MeAMY与VTA连接中的功能 男性的MeAMY-VTA投射可以逆转/缩小SA习得中的性别差异。这些实验将 让我做好准备，从功能上审问手段作为性别差异在奖赏中的中介作用 在本奖项的R00部分中，贯穿中脑边缘多巴胺通路。我的独立实验室将 伏核谷氨酸能传入调制的性别差异 并描述这些输入在性二态寻求毒品行为中的作用。在……里面 总而言之，这项在独立之路奖中提出的研究将揭示独立的和潜在的 成瘾和药物滥用的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，这个奖项提供的额外培训将为我启动一个独立的研究计划做好准备 在药物滥用的翻译模型中，从分子到电路，评估奖励中的性别差异。

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.