Glucocorticoid hormone entrainment of prefrontal cortex circadian function

University Of Colorado At Boulder, Boulder CO

Investigators

Abstract

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.