GSK3 regulation of suprachiasmatic neuronal excitability and light entrainment

Summary

Principal Investigator: JODI RENEE PAUL
Abstract: DESCRIPTION (provided by applicant): Circadian rhythms are approximately 24-hour cycles in behavioral and physiological processes, such as sleep/wake cycles and cognition. In mammals, these rhythms are endogenously generated and entrained to the external light cycle by the primary circadian pacemaker, the suprachiasmatic nucleus (SCN). A hallmark characteristic of SCN neurons is the daily rhythm in the spontaneous action potential frequency, with high activity during the day and low activity at night. These SCN firing rate patterns are critical for maintaining robust, consolidated behavioral rhythms, and persistent changes in SCN neuronal activity are involved light-induced behavioral shifts. Many of the ionic components underlying daily and light-responsive changes in SCN physiology have been described;however, the mechanism controlling expression of these currents is not known. Glycogen synthase kinase 3 (GSK3) is a serine-threonine kinase that is an emerging regulator of mammalian circadian rhythms and has been implicated in a variety of neurological, neurodegenerative, and psychiatric disorders. In the SCN, GSK3 exhibits daily rhythms in activity. Our recent work has shown that chronic GSK3 activation eliminates the typical day/night differences in SCN activity, with high, "day"-like activity at night, highlighting GSK3 a a previously unexplored regulator of SCN neurophysiology. The overall goal of this proposal is to examine the role of GSK3 activity in regulating SCN neuronal excitability and photic (light) entrainment of the circadian system, using circadian behavioral analysis, immunohistochemistry, real-time bioluminescence, and whole-cell electrophysiology in the presence of chronic GSK3 activation and following pharmacological inhibition of GSK3. The specific aims will test the hypotheses that: 1) GSK3 activity regulates SCN neurophysiological excitability through modulation of the persistent sodium current and 2) GSK3 mediates light- induced SCN excitability and phase-resetting. The results of the studies proposed here will expand upon the current understanding of GSK3's involvement in the circadian system, and provide novel insight into the mechanism controlling SCN membrane physiology. Furthermore, Because GSK3 has been implicated in numerous clinical disorders which also exhibit circadian disruption, a better understanding of the role of GSK3 in circadian regulation could lead to new treatment strategies for these disorders in the future.
Funding Period: -----------------201 - ----------------2015
more information: NIH RePORT

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. JHU Center for Neuroscience Research
    Alex L Kolodkin; Fiscal Year: 2013
  3. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
  4. Enduring Effects of Early-Life Serotonin Signaling
    Randy D Blakely; Fiscal Year: 2013
  5. HMS/CHB Center for Neuroscience Research
    Michael E Greenberg; Fiscal Year: 2013
  6. Genetics of Parkonsonism
    Jeffery Marvin Vance; Fiscal Year: 2013
  7. Udall Parkinson's Disease Center at Emory University: Circuitry to Therapy
    THOMAS N WICHMANN; Fiscal Year: 2013
  8. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
  9. Linking Molecular and Electrical Rhythms in the Brain's Biological Clock
    Jeffrey R Jones; Fiscal Year: 2013
  10. COBRE: The Delaware Center for Neuroscience Research
    Melissa A Harrington; Fiscal Year: 2013

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. JHU Center for Neuroscience Research
    Alex L Kolodkin; Fiscal Year: 2013
    ..abstract_text> ..
  3. Intellectual and Development Disabilities Research Center
    Marc Yudkoff; Fiscal Year: 2013
    ..5 million from NICHD). The Center includes an excess of 70 Penn faculty at 15 departments at the Schools of Medicine, Veterinary Medicine, Nursing, the Wistar Institute, and the College of Arts and Sciences. ..
  4. Enduring Effects of Early-Life Serotonin Signaling
    Randy D Blakely; Fiscal Year: 2013
    ..abstract_text> ..
  5. HMS/CHB Center for Neuroscience Research
    Michael E Greenberg; Fiscal Year: 2013
    ....
  6. Genetics of Parkonsonism
    Jeffery Marvin Vance; Fiscal Year: 2013
    ....
  7. Udall Parkinson's Disease Center at Emory University: Circuitry to Therapy
    THOMAS N WICHMANN; Fiscal Year: 2013
    ....
  8. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
    ..abstract_text> ..
  9. Linking Molecular and Electrical Rhythms in the Brain's Biological Clock
    Jeffrey R Jones; Fiscal Year: 2013
    ....
  10. COBRE: The Delaware Center for Neuroscience Research
    Melissa A Harrington; Fiscal Year: 2013
    ..Second, the Center will support a group of junior women faculty to become R01-funded investigators and advance to senior levels both academically and scientifically. ..
  11. Integration of sleep/wake network models across multiple temporal and spatial sca
    ANDREW JOHN PHILLIPS; Fiscal Year: 2013
    ..The proposed project will grant Dr. Phillips the necessary protected time to conduct research, achieve the necessary experience, and learn the requisite skills to achieve these long-term goals. ..
  12. Morehouse School of Medicine SNRP
    Peter R MacLeish; Fiscal Year: 2013
    ..To accomplish the above goals, we will provide effective administrative and scientific resource cores to facilitate the goals of this application. ..
  13. (INTRODUCTION) MECHANISMS OF ACCLIMATIZATION: FETUS AND ADULT
    Lawrence D Longo; Fiscal Year: 2013
    ....
  14. Glial Cell Regulation of Circadian Behavior
    F Rob Jackson; Fiscal Year: 2013
    ..Our proposed studies have significance for understanding the roles of glia and neuron-glia communication in health and many different neurological diseases. ..
  15. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  16. Vermont Center on Behavior and Health
    Stephen T Higgins; Fiscal Year: 2013
    ..S. public health. ..
  17. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  18. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  19. Alerations of Sleep and Circadian Timing in Aging
    Eve Van Cauter; Fiscal Year: 2013
    ..Core B (Methods and Analysis) will standard operating procedures for data collection, archival and analysis. Core C will assay peripheral levels of hormones, cytokines and other blood constituents. ..
  20. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  21. Alzheimer's Disease Research Center
    Douglas R Galasko; Fiscal Year: 2013
    ..It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research. ..
  22. Electric Studies of Excitation, Secretion &Contraction
    Bertil Hille; Fiscal Year: 2013
    ..Understanding the rhythmic secretory mechanisms of the pineal will make an important contribution towards treating sleep disorders, seasonal affective responses to short days, and loss of attention due to jet lag and shift work. ..
  23. Genetically-Encoded Tools for Manipulation of Ion Channel and Receptor Functions
    Edward S Boyden; Fiscal Year: 2013
    ....
  24. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  25. Regional, Synpatic, Cellular Modulation of Abeta Metabolism
    David M Holtzman; Fiscal Year: 2013
    ..abstract_text> ..
  26. Circadian dysfunction and GSK3 in neurodegenerative disease
    Karen L Gamble; Fiscal Year: 2013
    ..They will also lay the groundwork for translational studies designed to target this mechanism for proper therapeutic timing in dementia and neurological disease. ..