The development of sleep-wake rhythms and the search for elemental circuits in the infant brain

Abstract

Despite the predominance of sleep in early infancy, developmental science has yet to play a major role in shaping concepts and theories about sleep and its associated ultradian and circadian rhythms. Here we argue that developmental analyses help us to elucidate the relative contributions of the brainstem and forebrain to sleep-wake control and to dissect the neural components of sleep-wake rhythms. Developmental analysis also makes it clear that sleep-wake processes in infants are the foundation for those of adults. For example, the infant brainstem alone contains a fundamental sleep-wake circuit that is sufficient to produce transitions among wakefulness, quiet sleep, and active sleep. In addition, consistent with the requirements of a "flip-flop" model of sleep-wake processes, this brainstem circuit supports rapid transitions between states. Later in development, strengthening bidirectional interactions between the brainstem and forebrain contribute to the consolidation of sleep and wake bouts, the elaboration of sleep homeostatic processes, and the emergence of diurnal or nocturnal circadian rhythms. The developmental perspective promoted here critically constrains theories of sleep-wake control and provides a needed framework for the creation of fully realized computational models. Finally, with a better understanding of how this system is constructed developmentally, we will gain insight into the processes that govern its disintegration due to aging and disease.

Figure 1

Alternative views regarding the location of the fundamental “flip-flop” governing sleep-wake transitions. (A) Currently popular models depict sleep-promoting mechanisms located in the rostral hypothalamus (i.e., VLPO) and wake-promoting mechanisms located in the brainstem and caudal hypothalamus (e.g., LC, TMN). According to this model, a transection placed between the two sides of the flip-flop (e.g., a precollicular transection, denoted by the vertical dashed line), would disable the flip-flop. (B) Developmental considerations lead to a model that places the fundamental sleep-wake flip-flop entirely within the brainstem. Putative brainstem wake-promoting nuclei are largely located within the dorsolateral pontine tegmentum and include LDT, LC, and PB; sleep-promoting nuclei include PO and subLC. According to this model, precollicular transection (now denoted by the horizontal dashed line) does not disable the flip-flop, thereby allowing for cyclic alternations between sleep and wake. This brainstem flip-flop exhibits its greatest autonomy early in development; with age, the flip-flop interacts increasingly and bidirectionally with hypothalamic (and other forebrain) mechanisms to consolidate sleep and wake bouts, allow for the expression of sleep rebound after deprivation, and express circadian rhythmicity. Some of these forebrain circuits can influence sleep and wake states independently of one another, whereas others are likely to be at least partially overlapping.

Figure 2

Schematic depiction of state transitions from wake to quiet sleep to active sleep and back to wake in the early postnatal period in Norway rats. Bottom row: Behavioral state categories. Middle rows: Electromyographic (EMG) and behavioral components of the cycle. Skeletal muscle tone fluctuates between high muscle tone during wakefulness and atonia during sleep. At the onset of high muscle tone, wake behaviors are most prevalent, after which they wane and then disappear at the onset of quiet sleep. Twitch movements of the limbs, tail, head, and eyes, which occur in bouts, are observed after a period of behavioral quiescence and mark the onset of active sleep; twitches are also observed as phasic spikes in the EMG record. These two components are observed as early as P2 in rats and require only the brainstem for their full expression. Top row: Beginning at P11, the cortical EEG begins to exhibit delta activity. Even at P11, delta is expressed primarily during the period defined at earlier ages—based on EMG and behavior alone—as quiet sleep.

Figure 3

(A) Fragmented sleep and wake bouts in a P2 Norway rat (upper) in relation to the relatively consolidated bouts at P21 (lower). Note the different time scales in the two traces. (B) Mean sleep (filled bars) and wake (open bars) bout durations in rats at five postnatal ages. The horizontal lines indicate patterns of significant age differences in sleep and wake durations. Means are presented with standard errors. Adapted from Blumberg, M. S., Seelke, A. M. H., Lowen, S. B., & Karlsson, K. Æ. (2005). Dynamics of sleep-wake cyclicity in developing rats. Proceedings of the National Academy of Sciences of the United States of America 102, 14860–14864.

Figure 4

Log-survivor distributions of (A) sleep and (B) wake bout durations in Norway rats across the first three postnatal weeks. Plots also depict values for the day (red) and night (blue). Each plot is constructed from pooled data (620–2213 points per plot). Straight lines on semi-log plots indicate that the data follow an exponential distribution; deviations from a straight line in the wake bouts at P15 and P21 are indicative of power-law distributions. Also, by P15, increased wakefulness at night becomes evident in this nocturnal species. Adapted from Gall, A. J., Todd, W. D., Ray, B., Coleman, C., & Blumberg, M. S. (2008). The development of day-night differences in sleep and wakefulness in Norway rats and the effect of bilateral enucleation. Journal of Biological Rhythms 23, 232–241.

Figure 5

Effects of SCN lesions on sleep and wake bout distributions in Norway rats. Lesions (or sham surgeries) were performed at P8 with testing at P21. Log-survivor plots are from pooled data (658–937 points per plot). Sham (solid line) and lesioned (dashed line) pups were recorded during the day (red) and at night (blue). Insets present mean sleep bout durations for sham and lesioned pups during the day and at night. * Significant difference from the corresponding daytime value. n = 6 subjects per group. Means are presented with standard errors. Adapted from Gall, A. J., Todd, W. D., & Blumberg, M. S. (2012). Development of SCN connectivity and the circadian control of arousal: A diminishing role for humoral factors? PLoS ONE 7, e45338.

Figure 6

Sleep pressure and rebound in P2 Norway rats with and without precollicular transections. (A) Sagittal section of a P2 rat brain to show the anterior-to-posterior range of the transections, denoted by black lines. (B) Mean number of presentations of an arousing stimulus for each 5-min interval during the deprivation period for sham (filled squares) and transected (open circles) groups. In both groups, the number of presentations required to maintain arousal increased significantly over the 30-min deprivation period, indicative of sleep pressure. * Significant difference from the first 5-minute interval. (C) Mean sleep bout durations for three experimental groups during the baseline, sleep deprivation, and recovery periods. Only the Sham+Deprived group exhibited a significant increase in bout duration during the recovery periods, suggesting that neural tissue anterior to the transection is necessary for expressing sleep rebound. † Significant difference from Transected+Undeprived. * Significant difference from Sham+Deprived. Means are presented with standard errors. From Todd, W. D., Gibson, J., Shaw, C., & Blumberg, M. S. (2010). Brainstem and hypothalamic regulation of sleep pressure and rebound in newborn rats. Behavioral Neuroscience, 124, 69–78.

Figure 7

Proposed model of developmental and species differences in neural connections among retina, SCN, and ventral subparaventricular zone (vSPVZ) in Norway rats and Nile grass rats. Green lines: presumed excitatory connections releasing glutamate (GLU) and pituitary adenylate cyclase (PACAP). Red lines: presumed inhibitory connections releasing GABA and vasoactive intestinal peptide (VIP). Dashed lines denote developing or relatively weak connections. From Todd, W. D., Gall, A. J., Weiner, J. A., & Blumberg, M. S. (2012). Distinct retinohypothalamic innervation patterns predict the developmental emergence of species-typical circadian phase preference in nocturnal Norway rats and diurnal Nile grass rats. The Journal of Comparative Neurology, 520, 3277–3292.

Figure 8

Effects of precollicular transections and SCN lesions on day-night differences in sleep and wake bout durations in P2 Norway rats. (A) Mean sleep and wake bout durations for sham and transected pups during the day (red bars) and at night (blue bars). * Significant difference from corresponding daytime value. n = 6 subjects per group. Far right: The range of transections in the sagittal plane. Abbreviations: AC: anterior commissure; SCN: suprachiasmatic nucleus; Th: thalamus; SC: superior colliculus. (B) Mean sleep and wake bout durations for sham and SCN-lesioned pups during the day (red bars) and at night (blue bars). Surgeries were performed at P1. * Significant difference from corresponding daytime value. n = 5 subjects per group. Far right: Photograph of a coronal section showing the extent of the bilateral electrolytic SCN lesions in this experiment; the smallest (green-filled area) and largest (yellow-filled area) lesions are shown. Abbreviations: SCN: suprachiasmatic nucleus; 3V: third ventricle; MPOA: medial preoptic area; ox: optic chiasm; PaAP: Anterior part of parvicellular nucleus. Means are presented with standard errors. Adapted from Gall, A. J., Todd, W. D., & Blumberg, M. S. (2012). Development of SCN connectivity and the circadian control of arousal: A diminishing role for humoral factors? PLoS ONE, 7, e45338.

Figure 9

Summary of the relative developmental changes in ultradian and circadian sleep-wake rhythmicity and associated neural substrates in Norway rats.