The near-24th oscillations in neural, hormonal and metabolic activities, present in all mammals, are controlled by a biological clock which is intrinsic to the suprachiasmatic nuclei (SCN) of the ventral hypothalamus. Light is the primary signal responsible for resetting the clock. Light causes phase delays during early night and phase advances during late night, but has no effect during the day. The retinohypothalamic tract (RHT) is the primary pathway which transmits light to the SCN. In vitro studies have shown that shown that the cyclic nucleotide, cGMP, causes phase advances of the clock during the subjective night, the same period when the clock is sensitive to light. Therefore, it is likely that the cGMP/PKG transduction system is part of the phase shifting mechanism caused by RHT stimulation during late night. The pathway through which light entrains the circadian click is hypothesized to include; light more RHT stimulation more glutamate release more nitric oxide release more cGMP activity more transcriptional events more phase shift. The focus of this proposal is to examine the role of cGMP in phase shifts caused by RHT stimulation. The proposed Specific Aims are: 1) to determine if stimulation of RHT via the optic nerve resets the clock in a manner similar to the way light resets the behavioral activity rhythm; 2) to determine if the cGMP/PKG transduction system is stimulated by RHT; and 3) to determine if the phase shift induced by cGMP and RHT involves a transcriptional process.
