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Science 21 December 2001:
Vol. 294. no. 5551, pp. 2511 - 2515
DOI: 10.1126/science.1067716
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Research Articles

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

Achim Kramer,1* Fu-Chia Yang,1dagger Pamela Snodgrass,2dagger Xiaodong Li,2dagger Thomas E. Scammell,3 Fred C. Davis,2 Charles J. Weitz1ddagger

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.

1 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Biology, Northeastern University, Boston, MA 02115, USA.
3 Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
*   Present address: Institute for Medical Immunology, Humboldt University, 10098 Berlin, Germany.

dagger    These authors contributed equally to this work.

ddagger    To whom correspondence should be addressed. E-mail: cweitz{at}hms.harvard.edu

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