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Emerging evidence has highlighted that the gut microbiota plays a critical role in the regulation of various aspects of mammalian physiology and behavior, including circadian rhythms. Circadian rhythms are fundamental behavioral and physiological processes that are governed by circadian pacemakers in the brain. Since mice are nocturnal, voluntary wheel running activity mostly occurs at night. This nocturnal wheel-running activity is driven by the primary circadian pacemaker located in the suprachiasmatic nucleus (SCN). Food anticipatory activity (FAA) is the increased bout of locomotor activity that precedes the scheduled short duration of a daily meal. FAA is controlled by the food-entrainable oscillator (FEO) located outside of the SCN. Several studies have shown that germ-free mice and mice with gut microbiota depletion altered those circadian behavioral rhythms. Therefore, this study was designed to test if the gut microbiota is involved in voluntary wheel running activity and FAA expression. To deplete gut microbiota, C57BL/6J wildtype mice were administered an antibiotic cocktail via their drinking water throughout the experiment. The effect of antibiotic cocktail treatment on wheel running activity rhythm in both female and male mice was not detectable with the sample size in our current study. Then mice were exposed to timed restricted feeding during the day. Both female and male mice treated with antibiotics exhibited normal FAA which was comparable with the FAA observed in the control group. Those results suggest that gut microbiota depletion has minimum effect on both circadian behavioral rhythms controlled by the SCN and FEO respectively. Our result contradicts recently published studies that reported significantly higher FAA levels in germ-free mice compared to their control counterparts and gut microbiota depletion significantly reduced voluntary activity by 50%.
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This content will become publicly available on May 4, 2027
Is the FEO Food-Entrainable? Reexamining the Classic Fred Stephan Experiment Using Canonical-Clock–Less Period 1/2/3 Triple Knockout Mice
When nocturnal rodents are subjected to daytime restricted feeding, in which food is only available for a few hours per day, they typically become active a few hours before the onset of the scheduled mealtime. This so-called food-anticipatory activity (FAA) is controlled by an autonomous circadian pacemaker, which is independent from the central circadian pacemaker in the suprachiasmatic nucleus (SCN). Fred Stephan named this pacemaker the food-entrainable oscillator (FEO) because FAA re-entrains to a shifted feeding schedule. We recently developed a method to measure food-seeking nose-poking behavior by an operant feeding device and found that anticipatory food-seeking nose-poking for scheduled daily food availability shifts in parallel with phase-shifted environmental light-dark cycles, raising the possibility that anticipatory food-seeking behavior is controlled by an oscillator entrained to the environmental light-dark cycle. With this possible light-entrainability of the FEO, we revisited Stephan’s historical experiment—testing whether the FEO entrains to feeding cycle in the absence of a light-dark cycle without functional SCN—usingPeriod 1/2/3triple knockout (KO) mice, in which the canonical circadian oscillators in the SCN and peripheral tissues are disabled. KO mice were subjected to restricted feeding under constant darkness. The food-seeking nose-poking activity of a subset of the KO mice indeed occasionally entrained to the feeding cycle and re-entrained to a shifted feeding cycle. Despite our previous study showing that anticipatory food-seeking behavior shifted with the environmental light-dark cycle, these data demonstrate that it can also entrain to the feeding cycle in the absence of an environmental light-dark cycle, supporting Stephan’s observation that the FEO is indeed food-entrainable.
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- Award ID(s):
- 1931115
- PAR ID:
- 10681009
- Publisher / Repository:
- Sage Journals
- Date Published:
- Journal Name:
- Journal of Biological Rhythms
- ISSN:
- 0748-7304
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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