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日波动操作（昼夜节律）以及该节奏与环境日夜周期的同步。哺乳动物大脑的特定区域，即超平整核，负责协调大脑的昼夜节律。关于这种协调如何发生的知之甚少。该项目检查了前额叶皮层的昼夜节律功能，额叶皮层是一个涉及复杂思维的大脑区域，例如计划和决策，以及对情绪和情感的控制。该项目将测试特定激素（糖皮质激素）作为核上核与前额叶皮层之间的通信者的创新假设。该项目将采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。该项目还将使用前额叶皮层基因表达的尖端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的新了解及其在脑昼夜运动功能协调中的作用。这种新的理解可能会通过促进新的策略来打击受干扰的昼夜节律功能，例如随着夜班工作，喷气滞后，季节性极端，衰老和某些疾病而发生的重大利益。这项研究将通过与科罗拉多大学的学习与多样性中心的持续合作伙伴关系，为来自不同背景的高中，本科生和研究生提供出色的研究机会。这项研究的结果将通过校园，区域和国家科学会议和社区论坛上的研究团队演讲以及公共实验室网站上的帖子传播给科学界和公众。哺乳动物物种中晚期认知功能的中心。认知功能的强烈昼夜变化表明MPFC的操作受到昼夜节律的控制。 MPFC缺乏与大脑的主时钟上核（SCN）（SCN）的直接神经连接，但糖皮质激素受体的表达很高，支持皮质酮（Cort）参与MPFC节奏时钟基因表达的前景。初步数据显示了MPFC时钟基因表达的动态调制，该调制取决于Cort的昼夜循环模式的先前每日轮廓。此外，有条件的恐惧灭绝的MPFC依赖性记忆任务显示出表达的昼夜变化，而肾上腺切除术大鼠中没有。基于这些支持的初步数据，该项目将确定：1）CORT是否有助于MPFC节奏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依赖性恐惧的恐惧灭绝的正常夹带是必需的。 3）MPFC介导的条件恐惧灭绝的cort夹带取决于MPFC糖皮质激素受体的Cort激活和节奏的MPFC时钟基因表达。拟议的研究将为一群高中，本科生和研究生提供出色的科学培训机会。一系列途径将用于传播该项目的发现及其对社会的价值。