Abstract
Circadian clocks in many brain regions and peripheral tissues are entrained by the daily rhythm of food intake. Clocks in one or more of these locations generate a daily rhythm of locomotor activity that anticipates a regular mealtime. Rats and mice can also anticipate two daily meals. Whether this involves 1 or 2 circadian clocks is unknown. To gain insight into how the circadian system adjusts to 2 daily mealtimes, male rats in a 12∶12 light-dark cycle were fed a 2 h meal either 4 h after lights-on or 4 h after lights-off, or a 1 h meal at both times. After 30 days, brain, blood, adrenal and stomach tissue were collected at 6 time points. Multiple clock genes from adrenals and stomachs were assayed by RT-PCR. Blood was assayed for corticosterone and ghrelin. Bmal1 expression was quantified in 14 brain regions by in situ hybridization. Clock gene rhythms in adrenal and stomach from day-fed rats oscillated in antiphase with the rhythms in night-fed rats, and at an intermediate phase in rats fed twice daily. Corticosterone and ghrelin in 1-meal rats peaked at or prior to the expected mealtime. In 2-meal rats, corticosterone peaked only prior the nighttime meal, while ghrelin peaked prior to the daytime meal and then remained elevated. The olfactory bulb, nucleus accumbens, dorsal striatum, cerebellum and arcuate nucleus exhibited significant daily rhythms of Bmal1 in the night-fed groups that were approximately in antiphase in the day-fed groups, and at intermediate levels (arrhythmic) in rats anticipating 2 daily meals. The dissociations between anticipatory activity and the peripheral clocks and hormones in rats anticipating 2 daily meals argue against a role for these signals in the timing of behavioral rhythms. The absence of rhythmicity at the tissue level in brain regions from rats anticipating 2 daily meals support behavioral evidence that circadian clock cells in these tissues may reorganize into two populations coupled to different meals.
Highlights
Behavior and physiology in mammals are regulated by a multi-oscillatory circadian timekeeping system that is synchronized to local time by sensitivity to environmental time cues (‘Zeitgebers’)
LD cycles determine the timing of circadian rhythms when food is available ad-libitum, food intake is the proximate zeitgeber for most circadian oscillators outside of the suprachiasmatic nucleus (SCN) pacemaker, and dominates when schedules of food availability and LD are in conflict
When food was omitted on day 33, the bout of food anticipatory activity persisted through the expected mealtimes before decreasing
Summary
Behavior and physiology in mammals are regulated by a multi-oscillatory circadian timekeeping system that is synchronized (entrained) to local time by sensitivity to environmental time cues (‘Zeitgebers’). Light-dark (LD) cycles are typically viewed as the most powerful zeitgeber, as these dominate phase control of circadian oscillators in the suprachiasmatic nucleus (SCN), a master clock that regulates the timing of oscillators elsewhere in the brain and body, via neural, endocrine and behavioral pathways [1, 2, 3]. If food is restricted to the usual sleep phase, corresponding to the light period in nocturnal rats and mice, circadian clocks in peripheral organs and in many brain regions exhibit a marked shift in phase, as do physiological functions associated with these tissues [4, 5]. Circadian clocks and physiology in rats and mice sustaining complete ablation of the SCN entrain robustly to a daily mealtime [6, 7, 8]. LD cycles determine the timing of circadian rhythms when food is available ad-libitum, food intake is the proximate zeitgeber for most circadian oscillators outside of the SCN pacemaker, and dominates when schedules of food availability and LD are in conflict
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