DESCRIPTION (provided by applicant): This project seeks to increase our understanding of the specific mechanisms used to communicate phase- related information throughout the mammalian master circadian clock, the suprachiasmatic nucleus (SCN). Synchronization among the ~20,000 neurons of the SCN is a critical physiological feature, as desynchronization caused by shift work or abnormal light exposure has been linked to disease ranging from mood disorders to cancer. The way in which these SCN neurons communicate with one another to maintain synchronization across daily oscillations and in response to phase-shifting information transmitted from the retina is poorly understood. While complex, the SCN is likely a prime candidate for therapeutic intervention based upon its robustness and adaptability. In order for effective treatments to be developed for the variety of disorders that are linked to circadian disruption, however, an increased understanding of the dynamics of the SCN system is required. This project therefore aims to increase this understanding using optogenetic manipulation of the SCN. This technique allows for the fine manipulation of the firing rate of neurons within the SCN, or in specific cell-type populations of the SCN. In combination with real-time measurements of clock gene expression via bioluminescence in vitro or locomotor behavior in vivo, this manipulation allows for the effect of changes in firing rate frequency to be
examined. The project will focus on the question of how light information transmitted to the SCN via the retina is transduced as a signal across the subregions of the SCN- what type of neuropeptides may be involved in this transmission, and what role the duration of firing within each subregion may play in the encoding of circadian behavior. By answering these questions, the possibilities for therapeutic intervention into the disrupted circadian clock will be broadly expanded, as a greater knowledge of the sequence of events and main components of this signal transmission will allow for increased pharmacological manipulation.