The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker

doi:10.1073/pnas.0604189103

The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker

*Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
Departments of ^†Molecular Genetics and
^§Pathology,
^‡Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; and
^¶Exploratory Research for Advanced Technology, Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan

Contributed by Masashi Yanagisawa, May 19, 2006

Abstract

Temporal restriction of feeding can phase-shift behavioral and physiological circadian rhythms in mammals. These changes in biological rhythms are postulated to be brought about by a food-entrainable oscillator (FEO) that is independent of the suprachiasmatic nucleus. However, the neural substrates of FEO have remained elusive. Here, we carried out an unbiased search for mouse brain region(s) that exhibit a rhythmic expression of the Period genes in a feeding-entrainable manner. We found that the compact part of the dorsomedial hypothalamic nucleus (DMH) demonstrates a robust oscillation of mPer expression only under restricted feeding. The oscillation persisted for at least 2 days even when mice were given no food during the expected feeding period after the establishment of food-entrained behavioral rhythms. Moreover, refeeding after fasting rapidly induced a transient mPer expression in the same area of DMH. Taken in conjunction with recent findings (i) that behavioral expression of food-entrainable circadian rhythms is blocked by cell-specific lesions of DMH in rats and (ii) that DMH neurons directly project to orexin neurons in the lateral hypothalamus, which are essential for proper expression of food-entrained behavioral rhythms, the present study suggests that DMH plays a key role as a central FEO in the feeding-mediated regulation of circadian behaviors.

Footnotes

^‖To whom correspondence should be addressed. E-mail: masashi.yanagisawa{at}utsouthwestern.edu
Author contributions: M.M. and M.Y. designed research; M.M. and S.C.W. performed research; M.M., J.A.R., and K.T. analyzed data; and M.M. and M.Y. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

FEO,

food-entrainable oscillator;

RF,

restricted feeding;

FAA,

food-anticipatory activity;

ALF,

ad libitum feeding;

ZT,

zeitgeber time;

SCN,

suprachiasmatic nucleus;

DMH,

dorsomedial hypothalamic nucleus;

DMHc,

compact part of DMH;

NTS,

nucleus of the solitary tract;

AP,

area postrema;

DMV,

dorsal motor nucleus of vagus.