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The Levinson Emerging Scholars Program

Christoffer Amdahl - Biochemistry, Neurobiology

Christoffer Amdahl Christoffer is currently a senior majoring in Neurobiology and Biochemistry. He began work in the de la Iglesia lab sophomore year of college studying the Neurobiology of Circadian Rhythms. Currently, his project consists the examination of the phosphorylation state of Phosephodiesterase-5 and its role in the cGMP-mediated light induced phase advance that occurs in the Suprachiasmatic Nucleus. This will hopefully develop a better understanding of the neurochemical mechanisms underlying circadian rhythms, as well as the means to provide pharmacological treatment. After graduation, Christoffer plans to attend either medical school or graduate school while continuing to stay involved in scientific research. When not in lab, he enjoys eating, exercising, and playing the ukulele.

Mentor: Horacio de la Iglesia, Biology

Project Title: Role of Phosphodiesterase-5 in cGMP-Mediated Light-Induced Phase Advances of the Circadian Clock

Abstract: Circadian rhythms, such as the sleep-wake cycle, are governed by a circadian clock located in the suprachiasmatic nucleus of the hypothalamus (SCN). This clock is synchronized by the light-dark (LD) cycle and the cyclic-guanosine monophoshate (cGMP) pathway is known to mediate its phase advances. Phase-advancing light pulses increase the levels of cGMP in the SCN and inhibition of phosphodiesterase-5 (PDE5), the enzyme that degrades cGMP, by artificial drugs such as sildenafil, enhance light-induced phase advances. These inhibitors act by inducing PDE5 phosphorylation and converting it to phosphorylated-PDE5 (phPDE5). This evidence suggests that the inactivation of PDE5 through its phosphorylation could be a mechanism through which light induces phase advances, and that sildenafil utilizes the same mechanism to enhance phase advances upon light stimulation. I am testing this hypothesis by measuring PDE5 and phPDE5 in the SCN of mice treated with a phase-advancing light pulse. Mice are administered either a light or a dark pulse at the time that light causes phase advances. Animals are sacrificed at different times after the presentation of the pulses, their brains are dissected and alternate sections are processed for immunohistochemistry against either PDE5 or phPDE5. My hypothesis predicts an increase in phPDE5-expressing cells in light-treated animals. Future experiments will determine if sildenafil- induced enhancement of phase advances are mediated by further increasing phPDE5. My findings may lead to the development of pharmacological treatments to treat circadian rhythm disorders such as insomnia, fatigue, and jet lag, as well as to manipulate circadian rhythms to achieve periods of extended wakefulness and alertness.