The most important function of circadian clocks is the synchronization of bodily activities with the 24 hr light-dark (LD) cycle through a process called entrainment. The critical importance of entrainment to human health has been demonstrated in both human and animal studies. Desynchrony of the entrainment process produced in the real world by shift work or experimentally by chronic phase shifts of the LD cycle increases the incidence of many disease states including cancer, cardiovascular disease and metabolic disorders. Understanding how the etiology of the disorders produced by disruptions in entrainment will require understanding the neural mechanisms controlling entrainment in the master circadian clock located in the suprachiasmatic nucleus (SCN). The overall goal of the proposed research is to identify the neural mechanisms responsible for entrainment of circadian rhythms in the SCN. Remarkable progress has been made in understanding how the dorsomedial SCN functions as a molecular circadian clock as well as how the ventrolateral SCN responds to light however the neural mechanisms responsible for linking these two critical functions remains unclear. Perhaps this is because light has long been considered to reset the circadian clock instantaneously (i.e., non-parametric entrainment), resulting in the general assumption that the neural mechanisms within the SCN responsible for communicating light to the clock in the core would be of a very short duration. In contrast, we propose that the neural mechanisms that link these two important circadian functions operate over several hours and that GABA is the critical neurochemical messenger. These studies will test the hypotheses that the sustained activation of GABA receptors within the SCN mediates the phase shifting effects of light, the induction of clock genes within the SCN, and that the effects of GABA are mediated by GABA-A-TONIC and not by GABA-A-PHASIC or GABA-B receptors. If we confirm that the sustained activation of GABA receptors over several hours mediates the effects of light in the SCN, it seems likely that this same type of sustained activation of GABA receptors might mediate specific functions in other CNS sites as well. In addition, these studies will provide important new information on functions of GABA receptor subtypes and their possible interactions that should be relevant to GABA action throughout the CNS. Understanding how GABA acts in the brain is extremely important clinically because of the many drugs that target GABA receptors for diseases ranging from epilepsy to anxiety.
Human and animal research have found that desynchrony of the temporal organization of the body produces a wide range of health problems including increased incidence of cancer, cardiovascular disease and sleep-wake disorders that affect millions of people. Since these desynchronies often result from disruptions in the process of circadian entrainment it is critical to understand the mechanisms that underlie entrainment in the master circadian clock located in the suprachiasmatic nucleus. This project aims to identify these mechanisms and thereby provide an understanding of how circadian desynchrony can produce these pathologies.