Transient entrainment of a circadian pacemaker during development by dopaminergic activation in Syrian hamsters

Abstract

Maternal cues entrain a circadian pacemaker in fetal Syrian hamsters. These cues may act through dopaminergic activation of the fetal suprachiasmatic nucleus (SCN); injection of the dopamine D1 agonist SKF38393 to pregnant hamsters entrains activity rhythms of their pups and induces expression of c-fos in the fetal SCN. The aim of this study was to examine the ability of SKF38393 to entrain neonatal Syrian hamsters and to determine the age at which this effect is lost. SKF38393 injections given to two groups of pups at opposite times of day on postnatal days (PN) 1–5 entrained the pups’ activity rhythms to average phases that differed by 9.25 h. SKF38393 failed to establish different average phases when given on PN 6–10. Injection of SKF38393 on PN 1, but not PN 6, induced expression of Fos. These results demonstrate that dopaminergic activation is a potent entraining stimulus in neonatal hamsters and that its entraining effects, as well as its ability to induce Fos, are lost by PN 6. The phase established by dopaminergic activation was approximately opposite to that previously shown to be established by melatonin injections. Dopaminergic activation and melatonin may mimic separate but complementary maternal entraining signals which represent day and night.

Introduction

Mammalian circadian rhythms are regulated by a circadian pacemaker within the suprachiasmatic nucleus (SCN) of the hypothalamus. In adults, these rhythms are entrained to the environment primarily by the light-dark cycle. In fetuses, however, the pacemaker is functional before retinal innervation of the SCN 27, 32 and is entrained by maternal rhythms [6]. This finding suggests that in humans, as well as in rodents, the fetal circadian pacemaker and the rhythms they ultimately regulate, such as the sleep-wake cycle, may be influenced by maternal circadian rhythms or by drugs that mimic or antagonize the relevant maternal signals.

In rats and hamsters, the maternal SCNs are known to be required for normal maternal entrainment 7, 28. The identity of the specific maternal signal(s) is, however, unknown. Three stimuli have been shown to entrain litters born to SCN-lesioned mothers: injection of melatonin [8] or the dopamine agonist SKF38393 (36) to the pregnant mother in Syrian hamsters, and restricted feeding schedules imposed upon the mother in rats [37].

In the case of melatonin, a variety of evidence suggests that it is a physiologically important signal [5], including the observation that the effectiveness of exogenous melatonin is transient during development. In Syrian hamsters, entrainment is possible with melatonin injections to the pregnant mother or directly to pups on postnatal days (PN) 1–5, but not on PN 6–10 8, 16. In rats, the first two postnatal weeks is also the age when maternal entrainment ends 10, 17, 26, 30 and entrainment by light begins [13]. A response to light, measured as 2-deoxyglucose uptake or induced expression of c-fos within the SCN, can be seen within 48 h of birth 15, 22, 38, but it is not yet known if entrainment by light occurs at this time. In Syrian and Djungarian hamsters, induction of Fos protein is first seen on PN 5 and 3, respectively 12, 20, and changes in the number and distribution of immunoreactive cells continues for 2 weeks (where appropriate, embyonic, and postnatal ages have been adjusted to be consistent with the convention used in this article).

Similar to melatonin, entrainment by dopaminergic activation might also be transient during development. Although dopaminergic activation and light both induce c-fos expression within the SCN, a transition occurs during the first postnatal week as to which of these is most effective in doing so 38, 39. In hamsters, prenatal injections SKF38393 cause entrainment, but a preliminary study indicates that injections to adults do not 31, 36. The goals of the present study were to determine whether entrainment by dopaminergic activation extends beyond birth and if so, whether the entrainment ends within the first two postnatal weeks. In addition the study examined whether c-fos induction by SKF38393 is correlated with the drug’s ability to cause entrainment. Finally, the study tested the hypothesis that, if SKF38393 causes entrainment, the phase relationship it establishes is different from that established by melatonin. This result would be consistent with the suggestion that dopaminergic activation represents or mimicks a signal for daytime whereas melatonin represents a signal for nighttime [35].