Potentiation of photic circadian clock phase shifts

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DESCRIPTION (provided by applicant): Arousal and sleep deprivation can regulate circadian rhythms in multiple ways. One extremely important effect is the ability of these non-photic, higher level inputs to antagonize the synchronizing effects of light, as shown, for example, in studies where non-photic stimuli can block photic phase shift responses. We recently discovered that blocking the non-photic neuropeptide Y (NPY) input pathway to the suprachiasmatic nuclei (SCN) can potentiate photic phase shifting, suggesting that this pathway tonically suppresses the effects of light, and pharmacological treatments can release the animal from these inhibitory effects. We know that non-photic inputs to the circadian clock are represented by both NPY and serotonergic pathways. Remarkably, blocking both NPY and serotonergic inputs potentiates photic effects to an even greater degree, such that a 5 min light pulse is able to induce a 7 h phase shift of circadian rhythms of a treated hamster, as compared to a circa-1 h phase shift in an untreated hamster. This grant will build upon these findings of greatly potentiated light-induced phase shifts when the arousal-related NPY and serotonergic inputs are pharmacologically blocked. We will test these hypotheses: Hypothesis 1: NPY Y5 and serotonin 5HT1A receptors regulate the phase shifting effects of light at multiple phases throughout the subjective night. Hypothesis 2: Non-input inputs do not need to coincide with light, but can alter the response to light when presented within 1 h of light onset or offset. Hypothesis 3: NPY and 5HT inputs alter light-induction of per1 and per2 gene expression. The capability of NPY and serotonin antagonists to potentiate and agonists to attenuate the effects of light on the circadian system could be a potentially useful tool in clinical research. In cases of entrainment disorders, such as delayed or advanced sleep phase syndrome, potentiating the effects of light at one time while blocking effects of light at another phase might be an approach to correct the phase of entrainment. Symptoms of jet lag might be shortened in duration if resetting effects of light in the new time zone are potentiated. Shift workers might benefit from blocking the effects of light at night. The progress of cancer is slower in patients with enhanced circadian rhythmicity, a benefit that might accrue from better circadian entrainment