Melatonin And Prenatal Communication Of Circadian Phase

In mature rodents, light is the most potent signal for synchronization of endogenous circadian rhythmicity to environmental cyclicity. Direct and indirect pathways from the retina to the suprachiasmatic nucleus (SCN) are involved in the process of photic entrainment. During development, entrainment of the biological clock begins prior to the development of the retinohypothalamic tract. Indeed, studies in rats, hamsters, mice, and monkeys indicate that the biological clock in the SCN is functional (rhythmic) and entrained prior to birth (Figure 1, lower panel; for reviews see 13,14,53,56). Prenatal entrainment requires the presence of the maternal SCN, indicating that the mother plays an active role in the entrainment of her fetuses (15,51). The potency of the mother as an entraining cue (Zeitgeber) decreases during the first week after birth, coincident with the appearance of circadian sensitivity to light. Maternal communication of time-of-day information is thus thought to reflect a transient mechanism for entrainment which precedes the anatomical and functional development of photic entrainment mechanisms (for further discussion, see 78).

Reppert and Schwartz (52) removed various endocrine organs in an attempt to identify a hormonal signal necessary for entrainment of the rat fetus. Removal of the pituitary, ovaries, adrenals, thyroid/parathyroid or pineal (each surgical procedure performed in separate groups of animals) did not disrupt prenatal synchronization (although results with pinealectomy were somewhat unclear). An alternative strategy is to identify stimuli which can entrain the fetal circadian clock when given periodically during gestation to SCN-lesioned dams. Three treatments which can entrain the fetal clock have been identified in this way: restricted feeding, timed administration of D1-dopamine receptor agonist, and timed administration of melatonin.

In rats, periodic feeding of SCN-lesioned dams during gestation leads to fetal entrainment (76). Periodic feeding (4 hours food access per 24 hour day on gestational days 8-19) induces rhythmicity in maternal activity, body temperature, and likely in metabolic parameters and substrate availability. Precursor loading can alter fetal brain neurotransmitter levels (1), so periodic feeding may act in part through stimulating monoamine levels in the fetal brain.

A second manipulation that can entrain fetal rodents is periodic stimulation of D1-dopamine receptors. D1-dopamine receptor gene expression is high in the fetal SCN and activation of SCN D1-dopamine receptors induces c-fos gene expression (5,70,71,78,81,82). Other studies have shown that the dopaminergic activation of c-fos gene expression is brief, developmentally restricted to the prenatal and early neonatal period, and is dependent upon the D1-dopamine receptor (5,78,82). In view of the correlation between photic activation of c-fos gene expression and phase shifting of the adult SCN, these data suggested that activation of D1-dopamine receptors in the fetal SCN may lead to entrainment of the fetus. Indeed, treatment of pregnant, SCN-lesioned hamsters with the D1-dopamine receptor agonist SKF 38393 (8mg/kg once per day on GD 12-15) entrains fetal hamsters and induces c-fos gene expression in the fetal hamster SCN (71). More recently,Viswanathan and Davis (70) have shown that a single injection of SKF 38393 on gestational day 15 can entrain fetal hamsters. Several groups have described a transient dopaminergic input to the developing SCN, which may participate in fetal entrainment under physiological conditions (47,60, and references therein).

Timed administration of melatonin is the third "signal" capable of entraining the fetal circadian clock. Melatonin plays an important role in circadian organization of several non-mammalian vertebrates, and exogenous melatonin can influence circadian rhythmicity in a variety of mammals (see 74 and this volume for reviews). Fred Davis and colleagues have shown that melatonin is a powerful entraining stimulus for the fetus: as with SKF 38393, a single injection late in gestation can synchronize the fetal circadian clocks (14). Sensitivity to melatonin begins late in gestation and persists into the early neonatal period (13,14,16,23; Figure 6). The postnatal decline in sensitivity to melatonin parallels the postnatal decline in melatonin receptor binding in the Syrian hamster SCN (19).

Receptors for both dopamine and melatonin are expressed in the developing SCN. These receptors generally have antagonistic effects on signal transduction

Figure 6. Definition of a sensitive period for entrainment by melatonin. Each large circle 24 hours on the day of weaning, and each smaller circle around the perimeter represents the time of activity onset of one pup. Synchrony among pups receiving a treatment is indicated by a clustering of pup phases. Filled and open circles represent pups whose dams received melatonin at night and in the morning, respectively. Timing of melatonin administration in night groups is indicated by underlined M, while morning groups are indicated by M (not underlined). All pups were gestated and reared in dim constant light by dams receiving SCN lesions on gestational day 7. The length of the arrow within each circle represents the degree of synchrony within the population as assessed by the Rayleigh test. Significant synchrony among pups was established by 4-5 melatonin injections delivered late in gestation (GD 12-15) and in the early postnatal period (postnatal day [PD] 1-5). Injections earlier in gestation (GD 9-12) and later in postnatal life (PD 6-10) did not produce the same synchronizing effect. Saline injections at comparable periods were without effect (not shown). Note that injections of melatonin at opposite phases established average phases that were roughly opposite. melatonin doses were 10-100 ug per animal in pregnancy, and an equivalent amount to neonates (0.167 ug/g). Data from Refs. 13,16,23.

PD1-5 PD6-10

Figure 6. Definition of a sensitive period for entrainment by melatonin. Each large circle 24 hours on the day of weaning, and each smaller circle around the perimeter represents the time of activity onset of one pup. Synchrony among pups receiving a treatment is indicated by a clustering of pup phases. Filled and open circles represent pups whose dams received melatonin at night and in the morning, respectively. Timing of melatonin administration in night groups is indicated by underlined M, while morning groups are indicated by M (not underlined). All pups were gestated and reared in dim constant light by dams receiving SCN lesions on gestational day 7. The length of the arrow within each circle represents the degree of synchrony within the population as assessed by the Rayleigh test. Significant synchrony among pups was established by 4-5 melatonin injections delivered late in gestation (GD 12-15) and in the early postnatal period (postnatal day [PD] 1-5). Injections earlier in gestation (GD 9-12) and later in postnatal life (PD 6-10) did not produce the same synchronizing effect. Saline injections at comparable periods were without effect (not shown). Note that injections of melatonin at opposite phases established average phases that were roughly opposite. melatonin doses were 10-100 ug per animal in pregnancy, and an equivalent amount to neonates (0.167 ug/g). Data from Refs. 13,16,23.

mechanisms: D1-dopamine receptors are coupled to the stimulation of cAMP accumulation, while melatonin receptors are negatively coupled to adenylyl cyclase (54). This antagonism extends also to prenatal entrainment: the phase set by prenatal injection of SKF 38393 is opposite the phase established by prenatal injections of melatonin (70,71). It is possible that the three identified mechanisms for prenatal entrainment are actually interrelated, with dopamine representing a final common pathway. Periodic feeding may cause rhythmic stimulation of dopamine levels in the fetal SCN, while melatonin may inhibit synaptic release of dopamine. Melatonin inhibits dopamine release from rabbit retina and rodent hypothalamus (17,90), so an effect of melatonin on dopamine release within the fetal SCN is very plausible. This model predicts that both melatonin and dopamine will be ineffective in entraining animals that lack functional D1-dopamine receptors. Dopamine, but not melatonin, is expected to entrain mice lacking melatonin receptors. Unfortunately, direct assessment of circadian phase in fetal mice has not been possible to date (5). Postnatal assessment of circadian phase in mice promises to be a useful approach provided that the phase recorded after weaning is an accurate reflection of prenatal, rather than postnatal, events.

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