All ETDs from UAB

Advisory Committee Chair

Karen L Gamble

Advisory Committee Members

Rita M Cowell

Catherine M Fuller

Linda Overstreet-Wadiche

Martin E Young

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Circadian rhythms are 24-hour cycles in biological and behavioral processes. These cycles enable an organism to predict changes in its environment, like changes in food availability and seasonality. Although endogenously driven, these rhythms can entrain or synchronize to daily changes in the environment, allowing the animal to adapt. One way entrainment occurs is shifts in circadian phase following the presentation of nonphotic, or non-light, stimuli, such as exercise, arousal, or stress at certain times of day. The molecular mechanisms underlying nonphotic entrainment are poorly understood - specifically, how nonphotic cues alter excitability within the suprachiasmatic nucleus (SCN) of the hypothalamus, the clock center of the mammalian brain, to change the timing of circadian rhythms. This dissertation tests the hypothesis that nonphotic stimuli activate G protein-coupled inwardly-rectifying potassium (GIRK) channels which decrease neuronal excitability, modulating the timing of circadian rhythms. We show that not only is GIRK channel protein and function regulated in a circadian manner within the SCN, but it is responsible for maintaining daytime resting membrane potential of these neurons even in the absence of a nonphotic signaling cue. Mice lacking the GIRK2 subunit have altered circadian entrainment, corresponding to decreased neuropeptide Y (NPY, a nonphotic neurotransmitter) signaling within SCN neurons. Loss of GIRK channel signaling also inhibits exogenous melatonin-induced phase-shifting of behavioral rhythms and decreased firing of SCN neurons, indicating that GIRK channels are necessary for two different nonphotic neurotransmitters within the SCN - NPY and melatonin. Finally, activation of GIRK channels is sufficient to mimic a nonphotic phase shift, indicating that GIRK channel activation may be a conserved response within the SCN to nonphotic stimuli. This dissertation is the first to demonstrate a direct link between nonphotic neurotransmitters, a specific ion channel at the membrane, and subsequent regulation of circadian rhythm timing both within the SCN and in animal locomotor behavior.

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