All ETDs from UAB

Advisory Committee Chair

Karen L Gamble

Advisory Committee Members

Lori L McMahon

David C Knight

Martin E Young

Frank R Amthor

Mary M Boggiano

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The current set of studies addresses three main hypotheses. We first tested the hypothesis that NPY-induced phase advances are accompanied by persistent suppression of core circadian clock gene PER2 and are mediated by long-term depression of neuronal excitability in a phase-specific manner. We found that NPY induced phase advances in PER2::LUC cultures, as well as decreased neuronal firing in SCN slices, are largest when NPY is given in the early part of the day and PER2::LUC phase advances were blocked by depolarization with potassium chloride, suggesting that NPY-induced phase advances are mediated by long-term depression of neuronal excitability. The second goal of this dissertation was to test the hypothesis that endogenous rhythms of GSK3 phosphorylation is critical for rhythmic BMAL1 expression and normal amplitude and periodicity of the molecular clock in the SCN. We found chronic activation of GSK3 impaired rhythmicity of the GSK3 target BMAL1, and pharmacological inhibition of GSK3 enhanced the amplitude and shortened the period of PER2::luciferase rhythms in organotypic SCN slice cultures. GSK3 is a candidate mediator of circadian control of learning and memory since it regulates hippocampal synaptic plasticity and contextual memory. Therefore, the third goal of this dissertation was to test the hypothesis that the balance of phosphorylated GSK3β to de-phosphorylated GSK3β is rhythmically regulated in the hippocampus and is critical for normal rhythmicity of the hippocampal molecular clock, synaptic plasticity, and memory. We found that GSK3 inhibition resulted in a reduction in LTP magnitude specific to night recordings only, and a facilitation of spontaneous alternation isolated to day testing. These results indicate that circadian rhythmicity of hippocampal GSK3 inactivation state regulates day/night differences in memory, LTP magnitude, and molecular clock periodicity. In conclusion, collectively the results of this dissertation project highlight the importance of the circadian system in regulating the molecular clock, both within the SCN and extra-SCN oscillators such as the hippocampus, which can ultimately lead to downstream neurophysiological and behavioral changes.

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