Standards of evidence in chronobiology: A response

A number of recent studies have debated the existence and nature of clocks outside the suprachiasmatic nucleus that may underlie circadian rhythms in conditions of food entrainment or methamphetamine administration. These papers claim that either the canonical clock genes, or the circuitry in the dorsomedial nucleus of the hypothalamus, may not be necessary for these forms of entrainment. In this paper, we review the evidence necessary to make these claims. In particular, we point out that it is necessary to remove classical conditioning stimuli and interval timer (homeostatic) effects to insure that the remaining entrainment is due to a circadian oscillator. None of these studies appears to meet these criteria for demonstrating circadian entrainment under these conditions. Our own studies, which were discussed in detail by a recent Review in these pages by Mistlberger and colleagues, came to an opposite conclusion. However, our studies were designed to meet these criteria, and we believe that these methodological differences explain why we find that canonical clock gene Bmal1 and the integrity of the dorsomedial nucleus are both required to produce true circadian entrainment under conditions of restricted feeding.