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

Daily feeding schedules generate food anticipatory rhythms of behavior and physiology that exhibitcanonical properties of circadian clock control. The molecular mechanisms and location of foodentrainablecircadian 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 anull mutation of the circadian clock gene Bmal1 and that these rhythms can be rescued by virallymediatedrestoration 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 samelaboratory, appear to establish the DMH as the site of a Bmal1-dependent circadian mechanismnecessary and sufficient for food anticipatory rhythms. However, careful examination of themanuscript reveals numerous weaknesses in the evidence as presented. These problems aregrouped as follows and elaborated in detail: 1. data management issues (apparent misalignments ofplotted data), 2. failure of evidence to support the major conclusions, and 3. missing data andmethodological details. The Fuller et al results are therefore considered inconclusive, and fail toclarify the role of either the DMH or Bmal1 in the expression of food-entrainable circadian rhythmsin rodents.