Influence of Gonadal Hormones on Fear Extinction

描述（由申请人提供）：这是一份申请K01指导研究科学家发展奖的申请，题目是“性腺激素对恐惧消退的影响”。啮齿动物和人类的神经影像学研究表明，腹侧内侧前额叶皮层（vmPFC）对灭绝记忆的回忆至关重要。候选人将使用功能性核磁共振成像和心理生理学测量来检查性别和性激素变异对涉及灭绝回忆的大脑区域功能活动的影响。我们将测试两个假设：1)月经周期中雌激素水平升高会减弱消退回路的功能活性，特别是vmPFC，从而减弱消退能力；2)在消退回忆期间，黄体酮的使用会促进消退回路的功能活性，从而增强消退能力。为了验证这些假设，健康的人类志愿者将接受为期两天的恐惧调节和消除方案，同时使用功能磁共振成像测量大脑反应。皮肤电导反应将被测量并用作恐惧指数。拟议研究的资源由麻省总医院（MGH）精神神经成像研究计划、MGH/MIT/HMS atholas A. Martinos生物医学成像中心和MGH/MIT一般临床研究中心提供。候选人的直接目标是在功能MRI，认知神经科学和神经内分泌学方面获得深入的培训，并提高研究和伦理技能。候选人的长期职业目标是成为一名有专业知识的研究者，研究性腺激素对情绪刺激处理过程中大脑功能的影响。相关性：以恐惧增加为特征的焦虑症的患病率在女性中是男性的两倍。该提案将首先研究健康的男性和女性在学习不恐惧方面的差异，从而开始研究这些差异的神经生物学基础。本实验将探讨月经周期不同阶段的激素变化（即雌激素和黄体酮）对涉及安全记忆信号的大脑区域活动的影响。该提案还将研究黄体酮对增强大脑安全信号的影响。这项建议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。

DESCRIPTION (provided by applicant): This is an application for a K01 Mentored Research Scientist Development Award entitled "Influence of Gonadal Hormones on Fear Extinction." Rodent and human neuroimaging studies indicate that the ventral medial prefrontal cortex (vmPFC) is critical for extinction memory recall. The candidate will use functional MRI and psychophysiological measures to examine the influence of sex and variance of gonadal hormones on the functional activity of brain regions involved in extinction recall. Two hypotheses will be tested: 1) elevated estrogen levels during menstrual cycle will attenuate functional activity of the extinction circuit, specifically vmPFC, and thus extinction capacity will be reduced, and 2) administration of progesterone will facilitate functional activity of this extinction circuitry during extinction recall that will result in enhanced extinction capacity. To test these hypotheses, healthy human volunteers will undergo a two-day fear conditioning and extinction protocol while measuring brain responses using fMRI. Skin conductance responses will be measured and used as an index of fear. The resources for the proposed research are provided by Massachusetts General Hospital (MGH) Psychiatric Neuroimaging Research Program, the MGH/MIT/HMS Athinolas A. Martinos Center for Biomedical Imaging, and the MGH/MIT General Clinical Research Center. The immediate objective of the candidate is to obtain in-depth training in functional MRI, cognitive neuroscience, and neuroendocrinology and to enhance skills in research and ethics. The long-term career goal is for the candidate to become an established investigator with expertise to study the influence of gonadal hormones on brain function during processing of emotional stimuli. Relevance: The prevalence of anxiety disorders, characterized by increased fear, is twice as high in women relative to men. This proposal will begin to examine the neurobiological basis for these differences by first studying how healthy men and women may differ in learning not to fear. The experiments herein will investigate the influence of hormonal changes (i.e. estrogen and progesterone) during different phases of the menstrual cycle on the activity of brain regions involved in signaling memory for safety. This proposal will also examine the influence of progesterone administration on boosting the brain's signal for safety. Findings from this proposal may help the development of sex-specific treatments for anxiety disorders.