The circadian clock in the suprachiasmatic nucleus (SCN) is thought to drive daily rhythms of behaviour by secreting factors that act locally within the hypothalamus. In a systematic screen, we identified transforming growth factor (TGF)alpha as a likely SCN inhibitor of locomotion. TGFalpha is expressed rhythmically in the SCN, and when infused into the 3rd ventricle it reversibly inhibits locomotor activity and disrupts circadian sleep-wake cycles. These actions are mediated by epidermal growth factor (EGF) receptors, which we identified on neurons in the hypothalamic subparaventricular zone. Mice with a hypomorphic EGF receptor mutation exhibit excessive daytime locomotor activity and fail to suppress activity when exposed to light. These results implicate EGF receptor signalling in the daily control of locomotor activity, and they identify a neural circuit in the hypothalamus that likely mediates the regulation of behaviour both by the SCN and the retina.
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