Circadian rhythms are highly conserved physiological functions that are present in almost all living organisms. In mammals, circadian rhythms are synchronized to the environmental light:dark cycle by daily adjustments in the hypothalamic suprachiasmatic nucleus (SCN), the location of the master circadian pacemaker. We hypothesize that light entrainment of the circadian clock involves neural plastic adaptations in the SCN. The mechanism of neural plasticity has been intensively studied in the hippocampus and the dentate gyrus. However, the cell and molecular mechanism underlying circadian clock resetting in the SCN remains poorly understood. Thus, we sought to investigate whether modulators that are known to regulate neural plasticity in the hippocampus play a role in the signal transduction of circadian clock resetting. Light induced expression of tissue-type plasminogen activator (tPA) in the SCN, maximal induction was seen one hour following a light pulse at circadian time (CT) 16. A corresponding increase in the tPA proteolytic activity was also observed. tPA-STOPTM (an inhibitor of tPA)-infused animals exhibited attenuated light-induced phase delay of circadian wheel running activity. The levels of cyclin-dependent kinase 5 activators, p35 and p25 were decreased at Zeitgeber Time (ZT) 16, at ZT22 the levels were increased whereas, no change was observed at ZT6. The bi-transgenic animal, CK-p25 demonstrated increased phase delay at CT16 and attenuated phase advance at CT22 following transient overexpression of p25. SCN neurons expressing p25 co-localized with phosphorylated-extracellular signal-regulated kinase and Gastrin Releasing Peptide. This is one of the first studies to report the involvement of these neuromodulators in circadian light entrainment. Mounting evidence shows that circadian rhythm disturbances may be associated with increased health risks, such as jet-lag, cancer development, cardiovascular and metabolic disorders. The findings of this study have improved our understanding of the complex and intricate pathways involved in light entrainment and may lead to development of novel therapeutic avenues in treating circadian rhythm disturbances.  Ph.D
