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Neural Basis of Arousal Signaling for Non-Photic Resetting of the Circadian Clock

Moshirpour, M;

Input to the suprachiasmatic nucleus (SCN) from the intergeniculate leaflet (IGL) is necessary for non-photic entrainment. However, the underlying mechanisms of IGL activation remain unknown. There are several arousal centers in the brain that could be involved in bringing about non-photic entrainment. These include the lateral hypothalamus (LH) which contains clockprojecting orexin cells, and the cholinergic basal forebrain that directly communicates with the SCN. Even though arousal is the key component of non-photic entrainment, the relationship between the IGL and these arousal areas is unclear. We investigated the neural basis of arousal signaling by first studying the potential inputs to the IGL from the LH and the basal forebrain of Syrian hamsters. Projections to the IGL, from both the LH and the basal forebrain cholinergic cells were found. Next, we examined whether orexin is necessary and sufficient for non-photic phase shifting by both blocking orexin prior to an arousal-inducing protocol such as sleep deprivation and administering orexin in the IGL. It was found that orexin alone is not necessary or sufficient to cause shifts. Instead, it was found that dual administration of a glutamate receptor agonist with orexin is sufficient to cause significant shifts, suggesting an additive effect at the IGL. We next examined whether acetylcholine is necessary for non-photic entrainment. No attenuation of the arousal-induced response was observed by blocking acetylcholine at the IGL, suggesting that it is not necessary for non-photic entrainment, though it has been reported to be critical at the SCN level. Finally, accumulation of the sleep factor adenosine in the basal forebrain was mimicked as a potential signal for activating the basal forebrain. No significant phase shifts or cellular activation of the basal forebrain was observed after blocking adenosine at the basal forebrain. Taken together, the results present the first report of a dual role for orexin and glutamate in potentially gating the IGL’s non-photic inputs to the SCN.