Our long-term research objective is to understand the molecular mechanisms that initiate circadian gene expression following external stimulation. We will use the pineal gland to study signaling pathways because it has been extensively used to study signaling cascades and so provides an extensive knowledgebase for our studies. Our research proposal has two goals: (1) to understand the mechanisms by which norepinepherine (NE) controls Period1 expression and (2) to investigate the regulation of circadian "Clock" genes' expressions following external stimulation. First, since NE increases intra-cellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels, we will investigate the mechanisms by which cAMP and cGMP signaling pathways induce Period 1 mRNA levels. Since Period 1 is thought to be involved in the resetting of circadian rhythms, we will focus on the regulation of Period 1 expression in specific aims I and I1. Secondly, we will investigate whether or not other circadian "Clock" mRNA levels are induced by NE, cAMP, cGMP, or cAMP and cGMP co-stimulation. Besides its biological importance and interest, the use of pineal gland as a model, has promise for providing information that may be applicable to the prevention of neurodegenerative diseases, such as Alzheimer's disease, since it has been suggested that melatonin may play a role in neuroprotection. In addition, our studies have the pete" tial to address problems associated with jet lag, circadian-based sleep disorders, some neuropsychiatric illnesses, and shift work.