Scheduled meal accelerates entrainment to a 6-h phase advance by shifting central and peripheral oscillations in rats.

Travelling across several time zones requires a fast adjustment of the circadian system and the differential adjustment speeds of organs and systems results in what is commonly referred as jet lag. During this transitory state of circadian disruption, individuals feel discomfort, appetite loss, fatigue, disturbed sleep and deficient performance of multiple tasks. We have demonstrated that after a 6-h phase advance of the light-dark cycle (LD) scheduled food in phase with the new night onset can speed up re-entrainment. In this study, we explored the possible mechanisms underlying the fast re-entrainment due to the feeding schedule. We focused on first- and second-order structures that provide metabolic information to the suprachiasmatic nucleus (SCN). We compared (i) control rats without change in LD cycle; (ii) rats exposed to a 6-h phase advance of the LD cycle with food ad libitum; and (iii) rats exposed to the 6-h phase advance combined with food access in phase with the new night. We found an immediate synchronizing effect of food on stomach distention and on c-Fos expression in the nucleus of the solitary tract, arcuate nucleus of the hypothalamus, dorsomedial hypothalamic nucleus and paraventricular nucleus. These observations indicate that in a model of jet lag, scheduled feeding can favour an immediate shift in first- and second-order relays to the SCN and that by keeping feeding schedules coupled to the new night, a fast re-entrainment may be achieved by shifting peripheral and extra-SCN oscillations.

In a rat model of night work, activity during the normal resting phase produces desynchrony in the hypothalamus.

Internal synchrony among external cycles and internal oscillators allows adaptation of physiology to cyclic demands for homeostasis. Night work and shift work lead to a disrupted phase relationship between external time cues and internal rhythms, also losing internal coherence among oscillations. This process results in internal desynchrony (ID) in which behavioral, hormonal, and metabolic variables cycle out of phase. It is still not clear whether ID originates at a peripheral or at a central level. In order to determine the possible role of hypothalamic oscillators in ID, we explored with a rat model of "night work" daily rhythms of activity and clock gene expression in the hypothalamus. This study provides evidence that wakefulness and activity during the normal resting phase lead to a shift in the diurnal rhythms of c-Fos and induce a rhythm of PER1 in the arcuate and dorsomedial nucleus of the hypothalamus, both associated with metabolism and regulation of the sleep/wake cycle. Moreover, the number of orexin (ORX)-positive neurons and c-Fos in the perifornical area increased during the working period, suggesting a relevant switch of activity in this brain region induced by the scheduled activity; however, the colocalization of c-Fos in ORX-positive cells was not increased. In contrast, the suprachiasmatic nucleus and the paraventricular nucleus remained locked to the light/dark cycle, resulting in ID in the hypothalamus. Present data suggest that ID occurs already at the level of the first output projections from the SCN, relaying nuclei that transmit temporal signals to other brain areas and to the periphery.

Differential effects of a restricted feeding schedule on clock-gene expression in the hypothalamus of the rat.

Restricted feeding schedules (RFS) entrain digestive, hormonal, and metabolic functions as well as oscillations of clock genes, such as Per1 and Per2, in peripheral organs. In the brain, in particular the hypothalamus, RFS induce and shift daily rhythms of Per1 and Per2 expression. To determine whether RFS affect clock genes in extra-SCN oscillators in a uniform manner, the present study investigated daily rhythms of Per1, Per2, and Bmal1 expression in various hypothalamic regions. Wistar rats were entrained to daily RFS (2 h food access starting at ZT6, RFS) or fed ad libitum (C) for three weeks. Brains were sampled every 3 h starting at ZT0, and were processed with in situ hybridization. In response to RFS, Per1 expression showed a 3 h phase advance in the suprachiasmatic nucleus (SCN), while Per2 and Bmal1 remained unaffected. Per1 was triggered at ZT6, anticipating food access in both arcuate (ARC) and dorsomedial nuclei (DMH), and was unaffected in the ventromedial (VMH) and paraventricular (PVN) nuclei. In contrast, Per2 expression during RFS showed a marked postprandial peak in the PVN, was unchanged in the ARC, and was down-regulated in the DMH and VMH. The temporal patterns of Bmal1 expression were not significantly modified in RFS rats. RFS differentially affected clock-gene expression (phase change, up- or downregulation) depending on the combination of hypothalamic nuclei and targeted genes. Present data highlight that metabolic or temporal cues elicited by feeding modify the temporal organization in the hypothalamus and are not exclusive for a food-entrained oscillator.

Entrainment by a palatable meal induces food-anticipatory activity and c-Fos expression in reward-related areas of the brain.

Rats maintained under restricted feeding schedules (RFS) develop food-anticipatory activity and entrainment of physiological parameters. Food entrainment is independent of the suprachiasmatic nucleus and depends on food-entrainable oscillators (FEO). Restricted feeding schedules lead animals toward a catabolic state and to increase their food driven motivation, suggesting that in this process metabolic- and reward-related mechanisms are implicated. This study explored if motivation driven by a palatable meal is sufficient to produce food-entrainment. To address this question, we evaluated whether daily fixed access to a highly palatable meal entrained (PME) locomotor activity, serum glucose and free fatty acids concentrations in rats maintained without food deprivation. The entrained response of PME rats was compared with rats entrained to RFS. In a second experiment, we used c-Fos-IR to identify structures in the central nervous system involved with PME. Rats showed anticipatory activity to a daily palatable meal, with a lower intensity than rats entrained to RFS. Anticipatory activity persisted at least for four cycles after interrupting palatable meal, suggesting that this persistence depends on an endogenous oscillator. Glucose and free fatty acids were not entrained in PME rats. c-Fos expression in limbic system nuclei was in phase with PME time, but not in the hypothalamus. Results suggest 1) that food deprivation, i.e. a catabolic state is not necessary for the expression of anticipatory activity; 2) that an increase in the motivational state due to taste and/or nutritional contents of palatable meal is sufficient to entrain behavior; and 3) that structures in the limbic system are involved in this entrainment process. The present study indicates that metabolic and motivational mechanisms are involved in food entrainment, and suggests that the FEO may be a multi-oscillatory system distributed over different regulatory systems in the brain.