Date of Degree
PhD (Doctor of Philosophy)
Mark S. Blumberg
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. After connectivity among the SCN, DMH, and LC is established, we tested the functional role of each nucleus in the modulation of sleep and wakefulness. Infants cycle rapidly between states of sleep and wakefulness, resulting in fragmented bouts. Over development, these sleep and wake bouts consolidate and circadian rhythms become evident. Analyses of the statistical distributions of sleep and wake bouts have revealed dramatic changes in the dynamics of sleep-wake activity. Sleep bouts follow an exponential distribution throughout development. In contrast, wake bouts initially follow an exponential distribution, but transition to a power-law distribution around P15. In Experiments 5, 6, and 7, we explored the contributions of the LC, SCN, and DMH, respectively, to this developmental transition. We found that lesions of each area prevented the emergence of power-law wake behavior. Lesions of the SCN and DMH also prevented the expression of nocturnality. Altogether, these findings reveal that neural connections between the SCN and brainstem develop over the first postnatal week. After this connectivity is established, the SCN-DMH-LC pathway is critical for the normal expression of power-law wake behavior and circadian rhythmicity. We suggest that the development of the SCN-DMH-LC circuit is critical for pups to regulate arousal and gain independence from the mother and littermates.
Copyright 2011 Andrew Jason Gall