Behavioural neuroscienceAbnormal response of melanin-concentrating hormone deficient mice to fasting: Hyperactivity and rapid eye movement sleep suppression
Section snippets
Production of MCH null mice
All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center and were strictly in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Every effort was made to minimize the number of mice used in this study and their suffering at all times. Independent targeting of the MCH allele to produce MCH null mice has been previously described (Shimada et al., 1998). The first
MCH deficiency increases wakefulness
We characterized the sleep and wakefulness of MCH−/− mice from EEG/EMG records. The overall organization of vigilance states in MCH−/− mice during normal feeding resembled that of C57Bl6/J wild-type mice: both genotypes exhibited long, consolidated bouts of wakefulness, especially during the dark phase. Sleep episodes were similarly consolidated, particularly during the light phase. However, MCH−/− mice spent about 90 min more time awake compared with wild-type mice over the 24-h period (Table 1
Discussion
Indirect evidence suggested that MCH might modulate vigilance states (Kilduff and de Lecea 2001, Verret et al 2003, van den Pol et al 2004, Modirrousta et al 2005), and MCH-1 receptor antagonists decrease sleep, including REM sleep, and increase wakefulness (Ahnaou et al., 2008). Here we have demonstrated for the first time that, under baseline conditions, MCH−/− mice exhibit consolidated, increased wakefulness during the dark phase without any rebound in the light phase. Our data thus provide
Conclusion
In conclusion, our data reveal that the link between energy homeostasis and behavioral adaptation, including vigilance state regulation, involves MCH. Additional studies will be required if MCH-1 receptor antagonists are to be used in the treatment of obesity.
Acknowledgments
We thank D. Sierra and D. Koovakkattu for programming and data analysis, S. A. Dixon for technical support, and W. H. Koster and J. E. Krause, formerly of Neurogen Corporation, for unpublished results from preclinical and clinical studies with NGD-4715. M.Y. is an investigator of the Howard Hughes Medical Institute. J.T.W. was previously a fellow of the Medical Scientist Training program of the University of Texas Southwestern Medical Center at Dallas. This work has been supported in part by
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- 1
J.T.W. and C.M.S. contributed equally to this work.
- 2
Present address: Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.