The circadian clock in the suprachiasmatic nucleus (SCN) of the brain drives daily cycles of behavioral activity by rhythmically releasing secreted factors that act on receptors near the 3rd ventricle, through either a paracrine or synaptic mechanism. Current evidence indicates that the SCN has a dual action, with activating factors promoting locomotor activity at one phase and inhibitory factors blocking activity at another. The identity of these factors is unknown.
The aim of this proposal is identify SCN factors regulating locomotor activity, both those promoting behavioral activity and those inhibiting it. The strategy for doing so is divided into two parts. The first is aimed at generating, to the extent practical, a comprehensive collection of peptide and protein factors secreted by SCN cells by means of a secretion trap genetic screen in yeast. The second is the systematic evaluation of secreted SCN factors for a role in locomotor activity in hamsters, as predicted by the hypothesis. Known factors and those newly identified in the secretion trap will be tested for an effect on locomotor activity after chronic infusion into the 3rd ventricle. Any found to do so would be studied further to determine if they satisfy additional predictions for physiological involvement in the circadian regulation of locomotor activity. The discovery of these secreted SCN factors would make possible the identification of specific molecular pathways and neuronal circuits underlying circadian locomotor activity, about which virtually nothing is known. Knowledge of factors and receptors in an endogenous system mediating daily activity cycles might prove of great value in the treatment of neurological, sleep, or affective disorders in which cycles of rest and activity are disturbed.
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