Glucocorticoid hormone entrainment of prefrontal cortex circadian function

最佳的大脑功能取决于每天波动的操作周期(昼夜节律)，以及这种节奏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。关于这种协调是如何发生的，人们知之甚少。这个项目考察了前额叶皮质的昼夜节律功能，这是一个参与复杂思维的大脑区域，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的假设，即一种特定的激素(糖皮质激素)在视交叉上核和前额叶皮质之间充当通信者。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叶皮质的昼夜节律。该项目还将使用前额叶皮质基因表达的尖端操作来识别昼夜节律有助于优化前额叶皮质功能的机制。这些研究将导致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的新的理解。这一新的理解可能会对社会产生重大的好处，因为它可以促进对抗昼夜节律功能紊乱的新策略，例如夜班工作、时差、季节性极端、衰老和某些疾病。这项研究将通过与科罗拉多大学STEM学习与多样性中心的持续合作，为来自不同背景的高中生、本科生和研究生提供极好的研究机会。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陈述以及在公共实验室网站上的张贴来传播给科学界和普通公众。内侧前额叶皮质(MPFC)是哺乳动物物种高级认知功能的核心。认知功能的强烈昼夜变化表明，mPFC的运行受昼夜节律的控制。MPFC与大脑的主钟-视交叉上核(SCN)缺乏直接的神经联系，但有糖皮质激素受体的高表达，支持皮质酮(Cort)参与mPFC节律钟基因表达的调控。初步数据显示，mPFC时钟基因表达的动态调节依赖于先前每日皮质醇循环模式的先天分布。此外，依赖mPFC的记忆任务--条件性恐惧消退--表现出一种在摘除肾上腺的大鼠中所没有的表达的日变化。基于这些支持的初步数据，该项目将确定：1)皮质醇是否有助于mPFC节律时钟基因表达的夹带，2)适当时机的每日皮质醇脉冲对于正常夹带依赖于mPFC的条件性恐惧消退的日变化是必要的，以及3)皮质醇对mPFC介导的条件性恐惧消退的夹带取决于皮质醇对mPFC糖皮质激素受体的激活和mPFC时钟基因的节律性表达。这项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。将利用各种途径传播该项目的调查结果及其对社会的价值。

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.