The Cerebellum Harbors a Circadian Oscillator Involved in Food Anticipation

Abstract

The cerebellum participates in motor coordination as well as in numerous cerebral processes, including temporal discrimination. Animals can predict daily timing of food availability, as manifested by food-anticipatory activity under restricted feeding. By studying ex vivo clock gene expression by in situ hybridization and recording in vitro Per1-luciferase bioluminescence, we report that the cerebellum contains a circadian oscillator sensitive to feeding cues (i.e., whose clock gene oscillations are shifted in response to restricted feeding). Food-anticipatory activity was markedly reduced in mice injected intracerebroventricularly with an immunotoxin that depletes Purkinje cells (i.e., OX7-saporin). Mice bearing the hotfoot mutation (i.e., Grid2 ho/ho ) have impaired cerebellar circuitry and mild ataxic phenotype. Grid2 ho/ho mice fed ad libitum showed regular behavioral rhythms and day-night variations of clock gene expression in the hypothalamus and cerebellum. When challenged with restricted feeding, however, Grid2 ho/ho mice did not show any food-anticipatory rhythms, nor timed feeding-induced changes in cerebellar clock gene expression. In hypothalamic arcuate and dorsomedial nuclei, however, shifts in Per1 expression in response to restricted feeding were similar in cerebellar mutant and wild-type mice. Furthermore, plasma corticosterone and metabolites before mealtime did not differ between cerebellar mutant and wild-type mice. Together, these data define a role for the cerebellum in the circadian timing network and indicate that the cerebellar oscillator is required for anticipation of mealtime.

Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior

“…In conclusion, the present study shows that the FEO may depend on an oscillating neuronal network that consists of different cell groups in different locations in the brain with or without the active participation of clock genes (12,42,48) (Fig. S13).…”

“…Thus, the arcuate nucleus seems a possible candidate within the network of structures for driving FAA (40). Other possible candidates are the nucleus accumbens, the paraventricular nucleus of the thalamus, and the cerebellum (9,42). Clearly, more research needs to be done to define the nature of this food-entrained network.…”

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

“…Neurons exhibiting robust circadian rhythms that would be potentially capable of controlling circadian feeding rhythms are present in the Arc (1,32,37,54,81). Not only do Arc leptin receptors exhibit diurnal variation (25), but Arc LepR-B-expressing neurons receive and appear to integrate food-and energyrelated signals arising from diverse central and peripheral sites (9,17,45,88,95).…”

“…Furthermore, the Arc contains oscillators that maintain their intrinsic rhythms for several days in culture (1). The rhythms of some Arc oscillators are shifted in response to the anticipation of a restricted meal (54) or to fasting (32). Some are entrained to the photoperiod but, unlike those in the suprachiasmatic nucleus (SCN), exhibit peaks during the night (1).…”

A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

“…It was initially believed that only the suprachiasmatic nucleus was involved in generating circadian rhythms. However in mammals genes are expressed in circadian rhythms in hippocampus [30][31][32] , olfactory bulb 33 , cerebellum 34 and other regions 35 . Increased synaptic activity can be a marker of the initiation of activity within the sleep-wake cycle of animals, and our data suggest that oligophrenin-1-dependent increase in Reverbα transcription as a result of synaptic activity may be a means of entraining hippocampal circadian oscillations to activity signals from other parts of the brain.…”