Regulation of Daily Locomotor Activity and Sleep by Hypothalamic EGF Receptor Signaling

TLDR

The SCN circadian clock is believed to regulate daily behavioral rhythms by locally secreting factors within the hypothalamus. TGF‑α, a SCN‑derived inhibitor of locomotion, acts through EGF receptors on neurons in the hypothalamic subparaventricular zone. Rhythmic TGF‑α expression in the SCN suppresses locomotor activity and sleep‑wake cycles via EGF receptors, and mice with reduced EGF receptor function exhibit excessive daytime activity and impaired light‑mediated suppression, underscoring EGF signaling’s role in daily locomotor regulation.

Abstract

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