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-alpha (TGF-alpha) as a likely SCN inhibitor of locomotion. TGF-alpha 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Biological Clocks / drug effects
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Biological Clocks / physiology
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Body Temperature / drug effects
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Cerebral Ventricles / metabolism
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Circadian Rhythm / drug effects
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Circadian Rhythm / physiology*
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Cricetinae
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Darkness
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Female
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Hypothalamus / metabolism*
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Ligands
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Light
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Male
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Mesocricetus
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Mice
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Motor Activity* / drug effects
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Neural Pathways / physiology
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Neurons / metabolism
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Point Mutation
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Retina / metabolism
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Retinal Ganglion Cells / metabolism
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Signal Transduction
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Sleep / drug effects
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Sleep / physiology*
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Suprachiasmatic Nucleus / metabolism*
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Transforming Growth Factor alpha / administration & dosage
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Transforming Growth Factor alpha / genetics
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Transforming Growth Factor alpha / metabolism
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Transforming Growth Factor alpha / pharmacology
Substances
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Ligands
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Transforming Growth Factor alpha
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Epidermal Growth Factor
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ErbB Receptors