Circadian rhythms are reoccurring 24-h changes in biological and behavioral processes, controlled by the clock center of the brain, the suprachiasmatic nucleus (SCN) of the hypothalamus. Disruption of circadian rhythms is a common symptom of many neurological disorders including Huntington's disease, Parkinson's disease, and epilepsy. Although melatonin is commonly used as an over-the-counter treatment for sleep and circadian disruption, the mechanism of action at the membrane and its effects on the molecular clock remains unknown. Day-time melatonin administration advances the circadian clock in a manner similar to neuropeptide Y (NPY), known to mediate nonphotic signals such as exercise and stress. Based on this observation, NPY and melatonin may be acting on similar downstream targets. It has been shown that NPY can activate G protein- coupled inwardly-rectifying potassium (GIRK) channels in neurons of other brain areas, leading to membrane hyperpolarization. Both melatonin and NPY have been shown to hyperpolarize SCN neurons in a potassium- sensitive manner. GIRK channel activation is an ideal candidate mediator of the nonphotic effects of NPY and melatonin in the SCN. Additionally, GIRK channels may play a role in modulating day-night differences in SCN excitability, influencing photic (light) entrainment as well.
Three specific aims will use electrophysiological, molecular, and behavioral assays to test the overall hypothesis that GIRK channels mediate the inhibitory effect of NPY and melatonin in the SCN, phase shifting circadian rhythms in neuronal firing and locomotor behavior. The results of this project will fill a gap in our knowledge of how GIRK channels influence intrinsic electrical properties and time-of-day signal integration of SCN neurons, allowing entrainment to both light and nonphotic stimuli in the environment. This project will also provide information to develop innovative treatments for circadian disruption involving nonphotic strategies (such as melatonin, exercise or novel pharmaceutics aimed at GIRK) that are likely to yield enhanced compliance and efficacy compared to the commonly used light-therapy approach. Furthermore, this fellowship will enable me to formulate and test hypotheses, develop molecular/physiological techniques and scientific writing, all of which will be invaluable as I work toward my goal of developing an independent research program.
The purpose of this research is to determine the role of G protein-coupled inwardly-rectifying potassium channels in integrating multiple time-of-day signals within the suprachiasmatic nucleus, the master clock of the body that controls circadian function. This study will provide insight into the molecular mechanisms of melatonin and neuropeptide Y, and will have ramification for the use of melatonin as a chronotherapy for sleep disorders and circadian disruption.
|Hablitz, L M; Molzof, H E; Paul, J R et al. (2014) Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein-coupled inwardly rectifying (GIRK) channels. J Physiol 592:5079-92|