The developmental emergence of a wake-promoting pathway regulating ultradian and circadian rhythms in infant rats

Abstract

In mammals, circadian rhythms are controlled by an endogenous clock located in the suprachiasmatic nucleus (SCN). The SCN is part of a wake-promoting pathway in adults involving the dorsomedial hypothalamus (DMH) and locus coeruleus (LC), but little is known about how this circuit develops. Therefore, we examined the neural mechanisms underlying the development of circadian and ultradian sleep-wake rhythms.Circadian rhythms of sleep and wakefulness are exhibited by rats at postnatal day (P)2, but the influence of forebrain structures, including the SCN, has not been examined.In Experiment 1, although precollicular transections at P2 did not alter day-night differences in sleep and wakefulness, transections at P8 did eliminate these differences.In contrast, in Experiment 2, SCN lesions eliminated day-night differences in sleep and wakefulness at P2. These results suggest that the SCN exerts a humoral influence in newborns and gains neural control over brainstem structures over the first postnatal week.Based on the results of Experiments 1 and 2, we hypothesized that neural connections among the SCN, DMH, and LC develop over the first postnatal week. In Experiment 3, we used fluorescent tracers to reveal that connections within this circuit are strengthened and elaborated-and also become bidirectional-between P2 and P8.The results of Experiment 3 indicate that the SCN receives feedback from the LC.To explore the functional mechanisms by which the SCN receives this feedback, in Experiment 4, we deprived pups of sleep at P8 and used cFos to visualize brain areas that became active as a result of forced wakefulness. Our findings in intact pups and those injected with DSP-4, a neurotoxin that targets noradrenergic LC terminals, suggest that forced wakefulness activates the LC, which subsequently activates the DMH and SCN.