ABSTRACT
Transforming growth factor-alpha (TGF-alpha) is a candidate output signal of the hypothalamic circadian pacemaker. TGF-alpha is expressed in the suprachiasmatic nucleus (SCN) of rats, hamsters, and rhesus macaques [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5., X. Li, N. Sankrithi and F.C. Davis, Transforming growth factor-alpha is expressed in astrocytes of the suprachiasmatic nucleus in hamster: role of glial cells in circadian clocks, Neuroreport, 13 (2002) 2143-7., Y.J. Ma, M.E. Costa and S.R. Ojeda, Developmental expression of the genes encoding transforming growth factor alpha and its receptor in the hypothalamus of female rhesus macaques, Neuroendocrinology, 60 (1994) 346-59., Y.J. Ma, M.P. Junier, M.E. Costa and S.R. Ojeda, Transforming growth factor-alpha gene expression in the hypothalamus is developmentally regulated and linked to sexual maturation, Neuron, 9 (1992) 657-70.]. TGF-alpha reversibly inhibits wheel-running activity during long-term infusions into the third ventricle of hamsters (2 weeks, intracerebroventricular or ICV) [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.], and this effect appears to be mediated by the epidermal growth factor receptor (EGFR or ErbB-1) [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.]. Here, we demonstrate that this inhibitory effect is not restricted to wheel-running behavior or to mediation by the EGFR. Using direct observation, we found the effects of long-term TGF-alpha infusion (ICV, 12 microl/day, 3.3 microM) to be more general than previously reported. Other active behaviors such as grooming and feeding were reversibly inhibited and hamsters showed dramatic weight loss as a result of reduced feeding (34% of body weight over 19 days). TGF-alpha did not disrupt a non-behavioral rhythm, the rhythm in pineal melatonin. Wheel-running activity was also inhibited by another epidermal growth factor-like (EGF-like) peptide, neuregulin (NRG-1), that binds to different ErbB receptors. Like TGF-alpha, NRG-1 caused a significant weight loss. We also show that an acute injection of TGF-alpha inhibits activity (ICV, 5 microl, 3.3 microM over 2 min), with inhibition and recovery occurring over a few hours. Although the results are consistent with the proposed [A. Kramer, F.C. Yang, P. Snodgrass, X. Li, T.E. Scammell, F.C. Davis and C.J. Weitz, Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling, Science, 294 (2001) 2511-5.] role for EGF-like peptides in the daily regulation of activity, the actions of these peptides might also contribute to the behavioral etiology of diseases in which EGF-like peptides are expressed.
