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每天的波动运行周期（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殊区域，视交叉上核，负责协调大脑的昼夜节律。我们对这种协调是如何发生的知之甚少。这个项目研究了前额叶皮层的昼夜节律功能，这是一个涉及复杂思维的大脑区域，如计划和决策，以及情绪和情感的控制。该项目将测试一个创新的假设，即一种特定的激素（糖皮质激素）作为视交叉上核和前额叶皮层之间的通讯者。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的前额叶皮层昼夜节律。该项目还将使用前沿的前额叶皮层基因表达操纵来辨别昼夜节律有助于最佳前额叶皮层功能的机制。这些研究将导致对糖皮质激素生理学及其在脑昼夜功能协调中的作用的新认识。这种新的理解可以通过促进新的策略来对抗受干扰的昼夜节律功能，例如夜班工作，时差，季节性极端，衰老和某些疾病，从而对社会产生重大利益。该研究将通过与科罗拉多大学STEM学习和多样性中心的持续合作，为来自不同背景的高中，本科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的帖子传播给科学界和公众。内侧前额叶皮层（mPFC）是哺乳动物物种高级认知功能的核心。认知功能的昼夜变化表明mPFC的运作受到昼夜节律的控制。mPFC与视交叉上核（SCN）（大脑中的主时钟）缺乏直接的神经联系，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前景。初步数据显示，动态调制的mPFC时钟基因的表达，这取决于先前的每日配置文件的昼夜循环模式的CORT。此外，一个mPFC依赖的记忆任务，条件性恐惧消退，表现出昼夜变化的表达，是在肾上腺切除大鼠缺席。根据这些初步佐证数据，本项目将确定：1）CORT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mPFC依赖性条件性恐惧消退中昼夜变化的正常夹带是必要的，和3）mPFC-的CORT夹带介导的条件性恐惧消退依赖于CORT激活mPFC糖皮质激素受体和节律性mPFC时钟基因表达。拟议的研究将为高中，本科和研究生的多样化群体提供极好的科学培训机会。将利用各种渠道传播该项目的调查结果及其对社会的价值。