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

Circadian rhythms in mammals are regulated by a master circadian pacemaker located in the suprachiasmatic nucleus (SCN) [1,2]. This pacemaker mediates entrainment of circadian rhythms to daily light-dark (LD) cycles, but is not necessary for entrainment of circadian rhythms to daily feeding schedules [3-5]. Rats, mice and other species entrained to a LD cycle and restricted to a single meal (typically 2–4 h duration) at a fixed time each day exhibit increased locomotor activity beginning 1–3 h prior to mealtime. Once established (typically within a week of scheduled feeding) this daily rhythm of food anticipatory activity persists when meals are omitted for 2 or more days (i.e., activity remains concentrated near the expected mealtime). Food-anticipatory rhythms are most readily generated by feeding schedules with a stable periodicity in the circadian range (~22–31-h), and are not affected by complete ablation of the SCN. Therefore, a food-sensitive circadian timing mechanism regulating behavior must exist in the brain or periphery outside of the SCN [6-8]. This mechanism has been conceptualized as a food-entrainable oscillator or pacemaker, analogous to the light-entrainable pacemaker in the SCN.Efforts to localize food-entrainable circadian oscillators for behavior began over 30 years ago, but until the turn of the 21st century were limited to a few laboratories, and yielded primarily negative findings. With the advent of powerful new molecular biological techniques, and recognition of the importance of food as a time-cue for circadian oscillators outside of the SCN [9,10], more laboratories have undertaken work on the neurobiology of food-entrainment. One laboratory (Saper and colleagues) has now published two studies that, taken together, appear to have succeeded in localizing a brain site critical for the expression of food anticipatory rhythms. In the first study, Gooley et al [11] reported that ablation of ~70–90% of the dorsomedial hypothalamus (DMH), by loc