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Non‐photic phase shifting of the circadian clock: role of the extracellular signal‐responsive kinases I/II/mitogen‐activated protein kinase pathway

The master circadian clock, located in the suprachiasmatic nucleus (SCN), is synchronized to the external world primarily through exposure to light. A second class of stimuli based on arousal or activity can also reset the hamster circadian clock in a manner distinct from light. The mechanism underlying these non‐photic phase shifts is unknown, although suppression of canonical clock genes and immediate early genes has been implicated. Recently, suppression of one of the mitogen‐activated protein kinases (MAPK), namely extracellular signal‐responsive kinases I/II (ERK), has been implicated in phase shifts to dark pulses, a stimulus with both photic and non‐photic components. We investigated the involvement of the ERK/MAPK pathway in phase shifts in response to 3 h of sleep deprivation initiated at mid‐day. About three‐quarters of animals subjected to this procedure demonstrated large phase advances of about 3 h. Those that shifted exhibited a significant decrease in phosphorylated ERK (p‐ERK) in the SCN. Those animals that were perfused during the sleep deprivation also exhibited immunoreactivity for p‐ERK in a distinct portion of the ventrolateral SCN. Finally, injections of U0126 to the SCN to prevent phosphorylation of ERK significantly decreased levels of p‐ERK but did not produce phase shifts. These data demonstrate that a purely non‐photic manipulation is able to alter the activity of the MAPK pathway in the SCN, with downregulation in the SCN shell and activation in a portion of the SCN core.