Glucocorticoid hormone entrainment of prefrontal cortex circadian function

糖皮质激素夹带前额皮质昼夜节律功能

• 批准号: 1456706
• 负责人: Robert Spencer
• 金额: $ 54.18万
• 依托单位: University of Colorado at Boulder
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1456706&HistoricalAwards=false
• 关键词: Glucocorticoid; hormone; entrainment; prefrontal; cortex

Optimal brain function depends on a daily cycle of fluctuating operation (a circadian rhythm) and synchronization of that rhythm to the environmental day-night cycle. A specific region of the mammalian brain, the suprachiasmatic nucleus, is responsible for coordinating the brain's circadian rhythms. Little is known about how this coordination happens. This project examines the circadian function of the prefrontal cortex, a brain region involved in complex thinking, such as planning and decision-making, and the control of mood and emotions. The project will test the innovative hypothesis that a specific hormone (glucocorticoid hormone) serves as communicator between the suprachiasmatic nucleus and the prefrontal cortex. The project will use a systems biology approach to determine how glucocorticoid hormones regulate prefrontal cortex circadian rhythms in rats. The project also will use cutting-edge manipulations of prefrontal cortex gene expression to discern the mechanisms by which circadian rhythms contribute to optimal prefrontal cortex function. The studies will result in new understanding of glucocorticoid hormone physiology and its role in the coordination of brain circadian function. This new understanding could have significant benefit for society by promoting new strategies to combat disturbed circadian function, such as occurs with night-shift work, jet lag, seasonal extremes, aging, and certain disorders. The research will provide excellent research opportunities for high school, undergraduate, and graduate students from diverse backgrounds through an ongoing partnership with the University of Colorado's STEM Center for Learning and Diversity. Findings from this research will be disseminated to the scientific community and the general public through research team presentations on campus, at regional and national scientific meetings and community forums, and postings on a public lab web-site.The medial prefrontal cortex (mPFC) is central to the advanced cognitive function in mammalian species. Strong diurnal variation in cognitive function suggests that mPFC operation is under circadian control. The mPFC lacks direct neural connection with the suprachiasmatic nucleus (SCN), the master clock in the brain, but has high expression of glucocorticoid receptors, supporting the prospect that corticosterone (CORT) participates in the entrainment of mPFC rhythmic clock gene expression. Preliminary data show dynamic modulation of mPFC clock gene expression that depends on the prior daily profile of diurnal circulating patterns of CORT. Moreover, a mPFC-dependent memory task, conditioned fear extinction, displays a diurnal variation in expression that is absent in adrenalectomized rats. Based on these supporting preliminary data, the project will determine whether: 1) CORT contributes to entrainment of mPFC rhythmic clock gene expression, 2) an appropriately timed daily CORT pulse is necessary for normal entrainment of diurnal variation in mPFC-dependent conditioned fear extinction, and 3) CORT entrainment of mPFC-mediated conditioned fear extinction depends on CORT activation of mPFC glucocorticoid receptors and rhythmic mPFC clock gene expression. The proposed research will provide excellent scientific training opportunities for a diverse group of high school, undergraduate, and graduate students. A range of avenues will be used for dissemination of the findings of this project and their value to society.

最佳的大脑功能取决于波动运行的每日周期（昼夜节律）以及该节律与环境昼夜周期的同步。哺乳动物大脑的一个特定区域，即视交叉上核，负责协调大脑的昼夜节律。人们对这种协调是如何发生的知之甚少。该项目研究了前额皮质的昼夜节律功能，前额皮质是一个涉及复杂思维的大脑区域，例如计划和决策以及情绪和情绪的控制。该项目将测试一种创新假设，即一种特定的激素（糖皮质激素）充当视交叉上核和前额皮质之间的沟通者。该项目将使用系统生物学方法来确定糖皮质激素如何调节大鼠前额皮质昼夜节律。该项目还将利用前额皮质基因表达的尖端操作来辨别昼夜节律有助于最佳前额皮质功能的机制。这些研究将对糖皮质激素生理学及其在协调大脑昼夜节律功能中的作用产生新的认识。这种新的认识可以通过推广新的策略来对抗昼夜节律功能紊乱，例如夜班工作、时差反应、极端季节性、衰老和某些疾病，从而为社会带来重大利益。通过与科罗拉多大学 STEM 学习和多样性中心的持续合作，该研究将为来自不同背景的高中生、本科生和研究生提供绝佳的研究机会。这项研究的结果将通过研究团队在校园、地区和国家科学会议和社区论坛上的演讲以及在公共实验室网站上发布的帖子，向科学界和公众传播。内侧前额叶皮层 (mPFC) 是哺乳动物高级认知功能的核心。认知功能的强烈昼夜变化表明 mPFC 的运行受到昼夜节律的控制。 mPFC 缺乏与大脑主时钟视交叉上核 (SCN) 的直接神经联系，但糖皮质激素受体高表达，支持皮质酮 (CORT) 参与 mPFC 节律时钟基因表达的夹带的前景。初步数据显示 mPFC 时钟基因表达的动态调节取决于 CORT 昼夜循环模式的先前每日概况。此外，mPFC 依赖性记忆任务（条件性恐惧消退）表现出表达的昼夜变化，而肾上腺切除大鼠中则没有这种变化。根据这些初步支持数据，该项目将确定：1) CORT 是否有助于 mPFC 节律时钟基因表达的夹带，2) 适当定时的每日 CORT 脉冲对于正常夹带 mPFC 依赖的条件性恐惧消退中的昼夜变化是必要的， 3) mPFC 介导的条件性恐惧消退的 CORT 夹带依赖于 mPFC 糖皮质激素受体和节律性 mPFC 时钟基因的 CORT 激活 表达。拟议的研究将为不同的高中生、本科生和研究生群体提供极好的科学培训机会。将利用一系列途径传播该项目的研究成果及其对社会的价值。