A time memory engram embedded in a light-entrainable circadian clock

Abstract

A longstanding mystery in chronobiology is the location and molecular mechanism of the food-entrainable oscillator (FEO).^1,2,3 The FEO is an enigmatic circadian pacemaker that controls food anticipatory activity (FAA). The FEO is implicated as a circadian oscillator that entrains to feeding time. However, the rhythmic properties of the FEO remain a mystery in part due to technical limitations in distinguishing FAA from locomotor activity controlled by the primary circadian pacemaker in the suprachiasmatic nucleus (SCN). To overcome this limitation, we used the Feeding Experimentation Device version 3 (FED3) to measure food-seeking, nose-poking behavior. When food availability was limited to 4 h at night, mice exhibited strong anticipatory nose-poking behavior prior to mealtime. When food availability was moved to the daytime, mice quickly expressed daytime anticipatory nose pokes without displaying transients. Unexpectedly, the mice also maintained nighttime anticipatory nose pokes, even though food pellets were no longer dispensed at night. We next tested if food anticipation was directly encoded on a light-entrainable oscillator by shifting the light-dark cycle without changing mealtime. Anticipatory behavior shifted in parallel with the light-dark cycle, although meal timing was unchanged. Next, we tested whether encoding meal timing for anticipatory nose pokes required a functional SCN by studying Period 1/2/3 triple knockout mice with disabled SCN. Food anticipatory nose poking of Period knockout mice shifted in parallel with the light-dark cycle independent of a functional SCN clock. Our data suggest that food anticipation time is embedded in a novel, extra-SCN light-entrainable oscillator.

Keywords: calorie restriction; circadian mutant mice; entrainment; extra-SCN circadian pacemaker; food anticipation; food-seeking behavior; operant chamber; restricted feeding; reward; wheel-running activity.