Abstract
Mice fed a single daily meal at intervals within the circadian range exhibit food anticipatory activity. Previous investigations strongly suggest that this behaviour is regulated by a circadian pacemaker entrained to the timing of fasting/refeeding. The neural correlate(s) of this pacemaker, the food entrainable oscillator (FEO), whether found in a neural network or a single locus, remain unknown. This study used a canonical property of circadian pacemakers, the ability to continue oscillating after removal of the entraining stimulus, to isolate activation within the neural correlates of food entrainable oscillator from all other mechanisms driving food anticipatory activity. It was hypothesized that continued anticipatory activation of central nuclei, after restricted feeding and a return to ad libitum feeding, would elucidate a neural representation of the signaling circuits responsible for the timekeeping component of the food entrainable oscillator. Animals were entrained to a temporally constrained meal then placed back on ad libitum feeding for several days until food anticipatory activity was abolished. Activation of nuclei throughout the brain was quantified using stereological analysis of c-FOS expressing cells and compared against both ad libitum fed and food entrained controls. Several hypothalamic and brainstem nuclei remained activated at the previous time of food anticipation, implicating them in the timekeeping mechanism necessary to track previous meal presentation. This study also provides a proof of concept for an experimental paradigm useful to further investigate the anatomical and molecular substrates of the FEO.
Highlights
All mammals exhibit circadian patterns of behaviour and physiology regulated by a complex network of endogenous clocks and coordinated by the master pacemaker in the suprachiasmatic nucleus of the hypothalamus (SCN) in order to phase align to the solar day [1,2]
The current project examined whether neuronal activity stimulated by scheduled meals would persist in a sub-population of brain structures following the termination of the restricted feeding schedules, thereby highlighting the potential brain structure(s) housing the pacemaker of the food entrainable oscillator
Our results show that a number of hypothalamic and brain stem structures continue to show elevated c-FOS expression days after the termination of the restricted feeding schedule and return to ad libitum feeding
Summary
All mammals exhibit circadian (daily) patterns of behaviour and physiology regulated by a complex network of endogenous clocks and coordinated by the master pacemaker in the suprachiasmatic nucleus of the hypothalamus (SCN) in order to phase align to the solar day [1,2]. The behavioural output of this FEO exhibits canonical properties of circadian pacemaker control including: the requirement of a zeitgeber for initial entrainment, a limited range of entrainment falling within a circadian timeframe (,22–29 hrs) [6,7,8], persistence of precisely timed oscillations for several cycles during sustained food deprivation [9,10,11], and transient rather than immediate resetting after a change in meal time [12]. Many physiological processes undergo temporal realignment under this type of feeding schedule, the output of the FEO typically used as a behavioral measure is food anticipatory locomotor activity (FAA), which has a robust, high amplitude oscillation that is recorded automatically with minimal disturbance to the subject
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