Review

Standards of evidence in chronobiology: critical review of a report that restoration of Bmal1 expression in the dorsomedial hypothalamus is sufficient to restore circadian food anticipatory rhythms in Bmal1-/- mice

Ralph E Mistlberger¹ , Ruud M Buijs² , Etienne Challet³ , Carolina Escobar⁴ , Glenn J Landry¹ , Andries Kalsbeek⁵ , Paul Pevet³ and Shigenobu Shibata⁶

¹  Department of Psychology, Simon Fraser University, Burnaby, BC Canada

²  Instituto de Investigacíones Biomedicas, Universidad Nacional Autónoma de México, Mexico

³  Institut de Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France

⁴  Departamento de Anatomía, Fac de Medicina, Universidad Nacional Autónoma de México, Mexico

⁵  Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

⁶  Department of Pharmacology, School of Science and Engineering, Waseda University, Tokyo, Japan

author email corresponding author email

Journal of Circadian Rhythms 2009, 7:3doi:10.1186/1740-3391-7-3

Published:	26 March 2009

Abstract

Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibit canonical properties of circadian clock control. The molecular mechanisms and location of food-entrainable circadian oscillators hypothesized to control food anticipatory rhythms are unknown. In 2008, Fuller et al reported that food-entrainable circadian rhythms are absent in mice bearing a null mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virally-mediated restoration of Bmal1 expression in the dorsomedial nucleus of the hypothalamus (DMH) but not in the suprachiasmatic nucleus (site of the master light-entrainable circadian pacemaker). These results, taken together with controversial DMH lesion results published by the same laboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanism necessary and sufficient for food anticipatory rhythms. However, careful examination of the manuscript reveals numerous weaknesses in the evidence as presented. These problems are grouped as follows and elaborated in detail: 1. data management issues (apparent misalignments of plotted data), 2. failure of evidence to support the major conclusions, and 3. missing data and methodological details. The Fuller et al results are therefore considered inconclusive, and fail to clarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythms in rodents.