The Influence of Estrogen on the Fear Extinction Network in Humans

描述（由申请人提供）：焦虑症的患病率是女性的两倍。患病率升高的原因尚不清楚，部分原因是大多数动物研究只使用雄性，而大多数人类研究并没有将性别视为感兴趣的变量。这项建议将开始检查这些差异的神经生物学基础， 首先研究健康女性雌激素的自然波动如何影响静息态活动和恐惧消退网络（包括杏仁核，海马体和腹内侧前额叶皮层（vmPFC））的防御诱导反应。其他实验将涉及自然循环女性的雌激素的外源性操纵，以了解这些操纵如何与恐惧消退网络的功能激活相互作用。健康女性将在月经周期的不同时间点参与一个完善的恐惧调节和消除协议。将采用功能性MRI和心理生理学工具来检验两个总体假设：1）在月经周期中自然升高的雌激素水平将促进恐惧消退网络的静息状态活动和预防诱导的功能反应，并且将与增强的消退保持相关，以及2）向女性外源性施用雌激素将增强消退保持，这将与增强的静息态活动和在消退回忆期间该消退回路的预防诱导的功能反应性相关。他的提案中的发现可能有助于开发针对焦虑症的性别特异性治疗方法，例如通过使用基于药物的药理学药物来促进治疗期间的安全学习过程。

DESCRIPTION (provided by applicant): The prevalence of anxiety disorders is twice as high in women. The reason for this eleveated prevalence is unclear, partly because most animal research has used only males, and most human research has not considered sex as a variable of interest. This proposal will begin to examine the neurobiological basis for these differences by first studying how natural fluctuations of estrogen in healthy women may influence the resting-state activity and the extinction-induced reactivity of the fear extinction network, including the amygdala, hippocampus, and the ventromedial prefrontal cortex (vmPFC). Additional experiments will involve exogenous manipulations of estrogen in naturally cycling women to see how these manipulations may interact with the functional activation of the fear extinction network. Healthy women will participate in a well-established fear conditioning and extinction protocol at different points of their menstrual cycle. Functional MRI and psychophysiological tools wil be employed to test two overall hypotheses: 1) Naturally elevated estrogen levels during the menstrual cycle will facilitate the resting-state activity and extinction-induced functional reactivity of the fear extinction network, and will be associated with enhanced extinction retention, and 2) Exogenous administration of estrogen to women will enhance extinction retention, which will be associated with enahnced resting-state activity and extinction-induced functional reactivity of this extinction circuitry during extinction recall. Findings from his proposal may help develop sex-specific treatments for anxiety disorders, for example by using hormonal-based pharmacological adjuncts to facilitate the processes of safety learning during therapy.