Development of the circadian system in early life: maternal and environmental factors

The internal circadian clock of humans governs daily physiological functions, including the sleep/wake cycle and rhythms of the hormones melatonin and cortisol [1, 2]. In healthy adults and children, the central biological clock adheres to a 24-h cycle by entraining to environmental time cues, the strongest being light. Circadian disruption and dysregulation in adults are associated with a number of physical and mental health conditions, including insomnia, neurodegenerative disorders, metabolic disease, and psychiatric disorders [3–7]. Development of the circadian system begins in utero and continues throughout early life. Data from rodent studies indicate that circadian disruption during fetal development is associated with adult-onset cardiovascular disease, reduced bone mass and strength, glucose intolerance, insulin resistance, and mood disorder-related behaviors including anhedonia- and depression-like behaviors [8–12]. In human fetuses and infants, little is known about the links between circadian system maturation and health, as well as the factors that influence the development of an adaptive biological clock.

Sleep disruption during infancy is prevalent and persistent. Cross-sectional data show that 10–46% of infants ages 6–18 months exhibit some type of sleep disturbance (e.g., bedtime fussiness, difficulty falling asleep, frequent, and prolonged night awakenings) [13–17]. Persistence of infant sleep problems through the preschool years is common and can track into late childhood and adolescence [15, 17]. Results from previous studies indicate a relationship between parent-reported sleep difficulties and child psychosocial issues, including aggressive behavior, attention problems, anxiety, hyperactivity, and mood problems [17–22]. Additionally, lower cognitive performance and poor school functioning are associated with childhood sleep problems, suggesting that sleep issues may play a role in diminishing cognitive processes [23–25]. On the familial level, infant sleep problems are associated with higher maternal depression and poorer global health in both parents [14, 17, 26]. Identifying modifiable risk factors at the earliest stage of development provides an important opportunity to understand how to prevent and remedy infant sleep problems and related health conditions, both concurrent and those that emerge in the future.

The prevalence of infant sleep problems may be due to misalignment between environmental inputs and endogenous biological rhythms across the prenatal and post-natal periods that influence development of the circadian system. Human fetuses and infants mature in the context of an artificial light-saturated environment, and the acute and chronic effects of this circadian misalignment on development remain largely unknown. This comprehensive review will describe what is known about human circadian rhythms in fetal and infant development, as well as factors that influence sleep and the circadian system in early life. It will (1) discuss the two-process model of sleep regulation, a foundational framework for understanding the interaction between sleep homeostasis and the circadian rhythm; (2) review the fundaments of circadian physiology; and (3) present different proposed mechanisms underlying development of the circadian system (Fig. 1).

Light is the strongest zeitgeber to the maternal suprachiasmatic nucleus (SCN) and regulates the diurnal fluctuation of maternal hormonal time cues directly to the fetus through the placenta and indirectly to the infant through breast milk. Additionally, light entrains the infant SCN via the developing retinohypothalamic tract (RHT). These environmental and maternal signals interact with the fetus and infant to influence the development of the circadian system.

As first proposed by Borbély in 1982 [27], sleep regulation is governed by the interaction between a clock-dependent circadian process, Process C, and a sleep/wake dependent homeostatic process, Process S. Process C oscillates as an approximate 24-h rhythm, with the drive for sleep beginning in the evening and reaching its peak in the middle of the night, followed by a drive for wakefulness that rises in the early morning [28]. Process S is determined by the amount of prior wakefulness, such that the longer an individual is awake, the greater the “pressure” to sleep. Sleep pressure builds in an exponential fashion across the day and dissipates throughout time spent sleeping [29]. These two processes are independent but interact to control levels of alertness and sleep drive. As sleep pressure rises throughout the day, it is opposed by a stronger circadian drive for wakefulness. At bedtime, sleep propensity is promoted by the coordination of melatonin secretion and a high level of sleep pressure [30]. Melatonin is synthesized and released by the pineal gland and binds to MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN) to help synchronize the circadian rhythm [31]. As sleep unfolds across the night, sleep pressure dissipates; however, the increase in the circadian promotion of sleep results in consolidation until waking in the morning. The synergy of these two systems is essential to promote optimal sleep at night and wakefulness during the day, and misalignment results in reduced sleep quality and duration [32–35].

Newborns spend about 70% of their first few weeks after birth sleeping, and the timing of their sleep episodes is distributed equally throughout the 24-h day with no clear rhythm [36, 37]. At 2 weeks of age, infants sleep in approximately 4-h intervals [38]. As measured by actigraphy, Jenni and colleagues [39] observed day-night differences in rest-activity patterns within the first weeks of infancy (Fig. 2). By 5 weeks of age, there was emergence of an infradian rhythm, with a 25-h period as circadian rhythmicity began to appear [36]. At about 15 weeks, more consolidated wake and sleep episodes were apparent, and by 6 to 9 months of age most infants were able to sleep through the night, displaying at least 6-h consolidated sleep episodes [40–42]. Average total sleep duration across the first year of life remained about 14 h per day. However, it was the lengthening and timing of sleep and wake episodes, an increase in sleep during the night and an increase in wakefulness during the day, that matured with development. In other words, older infants, with more mature circadian regulation, were more likely to sleep during the night for longer durations than newborns. It should be noted, however, that alongside circadian system development, maturation of the sleep homeostatic process also plays a role in the emergence of this observed 24-h pattern in the first few months of life [40, 43]. Additionally, individual variability of sleep timing and duration is large [42], representing differences in the developmental manifestation of sleep-wake and circadian synchronicity.

Double plotted rest-activity patterns of three infants. The horizontal axis represents 48 h, black areas represent activity, and white areas depict rest episodes. Data were continuously collected in 1-min epochs via actigraphy over 6 to 12 months. Initially, post-birth, infants had weak day-night asymmetry, with sleep and wake occurring at all hours of the 24-h day. Infants 1 and 5 developed an ultradian pattern of rest and activity that emerged in the first few weeks of life, followed by more nighttime sleep consolidation and a regular daytime nap schedule. Infant 2 displayed a less robust ultradian rhythm in the first few weeks and more irregular daytime naps. These three infants demonstrate the interindividual variability in rest-activity patterns observed in early development. Note: Reprinted from “Development of the 24-h rest-activity pattern in human infants,” by O. G. Jenni, T. Doboer, and P. Achermann, 2006, Infant Behavior & Development, 29, p. 143–152. Copyright 2005 by Elsevier Inc. Adapted with permission.

Circadian (Latin for “circa diem,” meaning “around a day”) rhythms are endogenous biological rhythms within organisms that oscillate in the absence of environmental time cues, entrain to environmental signals, and remain stable in environments with fluctuating temperatures [44]. For biological processes to occur at the appropriate time in the proper sequence, organisms must be able to synchronize to and predict their external environment. This ‘temporal framework’ allows organisms to anticipate daily changes and optimize their behavior and physiology in advance of the daily demands of the light-dark cycle [1].

At the molecular level, the SCN maintains 24-h rhythmicity through positive and negative transcriptional-translational feedback loops of clock genes [45]. In mammals, the positive feedback loop is initiated during the biological day through positive regulating genes Bmal1 (Brain and muscle Arnt-like factor) and Clock (Circadian locomotor output cycle kaput) and their protein products [1, 46]. Within the nucleus, proteins BMAL1 and CLOCK heterodimerize and bind to E-box response elements within promoter regions of negative regulating genes Per (Per1 and Per2) and Cry (Cry1 and Cry2), inducing their transcription. Per and Cry mRNA diffuse into the cytoplasm where they are translated into PER and CRY proteins by ribosomes. At night, PER and CRY proteins in association with casein kinase 1 and other proteins translocate back into the nucleus with the help of GAPVD1, a cytoplasmic trafficking factor, where they inhibit CLOCK:BMAL1 transcriptional activity and subsequently close the negative feedback loop [47]. Casein kinase 1 also mediates proteasome degradation of PER through phosphorylation, thus lifting the inhibition of BMAL1 and CLOCK and allowing a new cycle of positive transcriptional activity to commence [48]. The CLOCK:BMAL1 complex also drives the transcription of Rorα (retinoic acid receptor-related orphan receptor α) and Rev-Erbα (reverse erythroblastosis virus α) genes, which serve as activators and inhibitors of Bmal1 transcription respectively [45]. This second feedback loop in conjunction with the previously described loop is responsible for a robust 24-h oscillatory molecular circadian cycle.

Although the mammalian molecular clock was first identified in the SCN in the late 1990s, subsequently the presence of an operational molecular clock has been observed in many tissues (“peripheral oscillators”) throughout the body [1]. Importantly, however, the circadian system is organized in a hierarchal fashion, with the SCN of the anterior hypothalamus serving as the master clock that works to synchronize peripheral oscillators [49]. SCN lesioned rodents lack circadian activity rhythms, and implantation of new SCN neural grafts is sufficient to restore circadian expression with a period length relative to the new SCN [50]. Thus, the SCN is the central driver of overt circadian rhythms.

In mammals, the SCN is comprised of a dorsal shell of neurons that express the neuropeptide arginine vasopressin (AVP) surrounding a ventral core composed of vasoactive intestinal polypeptide (VIP) expressing neurons [51]. When placed in culture, in vitro SCN neurons maintained a robust 24-h rhythm of Per1 clock gene expression for more than 30 days [52]. Conversely, peripheral tissues that underwent the same treatment only retained Per1 rhythmicity for less than a week, suggesting a loss of synchronization in the absence of rhythmic signals from the SCN. Furthermore, when rats experienced a 6-h delay or advance in their light:dark (LD) 12 h:12 h cycle, their SCN neurons in vitro shifted rapidly in response to environmental light, while peripheral cells had a less adaptive response, indicating that these damped oscillators required an external circadian signal for both rhythmicity and adjustment [52]. These peripheral oscillators are subordinate to the SCN and have been demonstrated in vivo in many tissues including various brain regions [53–55]. It is noteworthy that the phase of oscillatory clock gene expression can vary between different peripheral oscillators and the SCN [56–58]. Therefore, one role of peripheral oscillators is likely to transduce a daily environmentally entrained timing signal from the SCN into the appropriate molecular oscillatory phase for optimal daily function of each tissue [59].

Light is the strongest zeitgeber (“time giver”) of the circadian system. Because the average SCN oscillation in humans is greater than 24 h (approximately 24.15 h), a daily reset is necessary to prevent the endogenous oscillation from drifting too far from the environmental light:dark cycle [60]. Through the retinohypothalamic tract (RHT), a neuronal pathway from the retina to the SCN, the SCN receives photic information that enables it to entrain to the light-dark cycle. This neuronal pathway consists of a special subset of retinal ganglion cells (intrinsic photosensitive retinal ganglion cells) that are exquisitely sensitive to low light levels, especially in the blue portion of the visible spectrum [61]. The SCN transmits this perceived time-of-day information via neural and hormonal signals to peripheral clocks located in brain areas outside of the SCN, as well as to most organs including the pancreas, liver, kidney, and heart [1, 56, 62–64]. The coordination of the SCN with its peripheral oscillators results in necessary and time-of-day appropriate physiological and behavioral outcomes [65]. It should be noted, however, that RHT stimulation of the SCN in response to light at night triggers a phase shift in SCN oscillation as the SCN adjusts its timing to an unexpected environmental light:dark cycle stimulus [66]. This inappropriate phase adjustment provides a major source of circadian disruption to the body.

The physiology of the SCN cannot be directly assessed in humans, and therefore studying output rhythms of the clock is necessary to determine the timing of the circadian rhythm. Measurable outputs, known as circadian phase markers, include melatonin, cortisol, and core body temperature. Timing of the internal clock is established through measurements of its period, the time necessary to complete a full oscillation, and phase, the state of an oscillation at a specific point in time [67].

Melatonin secretion is regulated by the SCN via a multi-synaptic pathway: from the SCN, neurons project to the superior cervical ganglion (SCG) and then to the pineal gland, which synthesizes and secretes melatonin [2]. Light exposure during the biological night results in rapid suppression of melatonin through this multi-synaptic pathway [68]. In adult humans, melatonin levels increase in the evening, peak during the middle of the night, and return to low levels in the morning where they remain throughout the day.

Cortisol is secreted from the adrenal glands in response to the pituitary gland releasing adrenocorticotropic hormone (ACTH). The circadian sensitivity of the adrenal gland to ACTH is regulated via a multi-synaptic neural output pathway from the SCN [2]. Cortisol secretion is lowest during the early night, begins to increase several hours before awakening, and peaks in the morning within 30–45 min after awakening. Of note, the cortisol awakening response (CAR) is a separate process that is superimposed on the underlying circadian peak of cortisol secretion [69]. It has been hypothesized that the magnitude of the morning CAR is associated with anticipation of stressors for the upcoming day [70].

Core body temperature peaks during the day and reaches its nadir in the middle of the night, which typically aligns with the sleep midpoint [71, 72]. Data from well-controlled studies indicate that the evening rise in melatonin prompts the nocturnal decrease in core body temperature through distal vasodilation and subsequent heat loss [73, 74].

There is growing support for the feasibility of measuring clock gene expression in human peripheral tissues as a useful circadian phase biomarker. Samples studied for these assessments include white blood cells, skin, oral mucosa, colon cells, adipose tissue, and post-mortem brain tissue [58]. Determining clock gene expression in peripheral tissues provides a method to monitor both central and peripheral clock regulation. Researchers are currently working towards validating gene expression from noninvasive skin samples as a biomarker of molecular clock phase to utilize in the rising field of circadian medicine [75].

In the context of post-modern electric lighting environments, pregnant women and infants face daily challenges of circadian disruption, and the associated early developmental outcomes remain poorly understood. In a case study of an infant who was breastfed and was only exposed to natural light for the first 6 months of life, measurable outputs of circadian rhythmicity appeared more rapidly than previously reported—the temperature rhythm was observed at 1 week of age, rhythms of wake and melatonin secretion at sunset emerged at day 45, and nighttime sleep onset aligned with sunset by day 60 [139]. This finding suggests that infants growing in the natural world with no electric lighting results in more favorable circadian-related developmental outcomes. Longitudinal studies to determine how maternal and environmental signals interact with circadian system development, such as breast milk and the light/dark cycle (Fig. 1) are necessary to establish what circadian cues to prioritize in prenatal and post-natal maturation.

Research in the field of circadian rhythm development has centered on two developmental timepoints, the prenatal and post-natal periods. As previously discussed, rhythms in the prenatal stage are influenced by maternal signals while rhythms in the post-natal stage are guided by environmental signals that the infant is exposed to as well as a maternal connection via breast milk. Although these two periods are distinct, they should not be treated as unconnected—prenatal development likely sets the stage for healthy post-natal development. Few studies have followed women and fetuses from pregnancy through early development in post-natal life. Capitalizing on such longitudinal data would allow examination of how factors during pregnancy may impact later development.

Although the multi-dimensional construct of “sleep health” as measured by self-reports and actigraphy has received considerable attention in the past decade [140–142], “circadian health” is a construct that is presently not well-defined, especially in the context of development. In part, this may be due to the demands of reliable measurement of circadian outputs, such as cortisol, melatonin, and core body temperature, but also reflects less developed conceptualization of a full distribution of core behavioral and physiological circadian features from good to poor. The SCN is complex with multiple neuronal and glial cell types, as well as different subregions and outputs. Therefore, within the SCN there is likely not a single biomarker that would reflect good circadian health. Understanding of how the SCN communicates with peripheral clocks is rapidly advancing based upon animal and adult human data; however, a similar appreciation is limited across development. Indeed, a significant component of circadian health may be at the level of communication between the SCN and peripheral clocks through entrainment signals. Additionally, most circadian research centers on how circadian systems respond to perturbation rather than how to create optimal environments for good circadian health. Also, current studies focus on the time course of clock outputs to quantify circadian clock development; however, with few longitudinal studies available, it is difficult to determine if early rhythms are sensitive predictors of an adaptive system later in life. Other features indicating optimal circadian system maturation may include robustness of rhythms, adaptability of the clock to changing environments, and consistency of rhythms. Future developmental research should consider not only clock outputs but also such metrics in early life that may predict circadian health across the lifespan.

Pregnant women, mothers, and other infant caregivers serve as gatekeepers to external factors that influence circadian system development. Conventional behaviors in our post-modern world can result in conflicting temporal time cues for developing fetuses and infants. During pregnancy, a woman’s physiological signals set time-of-day cues for the fetus, and exposure to light at night results in a desynchronized circadian system that may disorganize the fetus’ circadian development and adaptation to environmental stimuli. Environmental lighting may also impact the developing infant through direct and indirect signals. For example, infants sleeping in a darkened room during daytime naps or exposed to light at night during feedings may experience a misperception of the time-of-day. Also, mothers breastfeeding at night may turn on an electric light or use a blue light-enriched device, which likely suppresses melatonin and other nighttime hormones found in breast milk, thus dampening maternal time cues to the infant’s circadian clock. Further, data suggest that infants who are fed formula do not benefit from the diurnal fluctuation of hormones present in breast milk. Additionally, women who pump may record the date but not the time-of-day that milk was expressed, which can result in infants receiving milk at a non-optimal circadian time. That is, if a woman feeds her infant milk in the evening that she previously pumped during the day, the infant will not receive nighttime hormonal time cues such as melatonin. The outcome of these mismatched signals and how they interact in early development and beyond remain unknown. One important question illustrating this type of interaction is if an infant is fed milk containing melatonin during the night but is exposed to artificial light. Which time cue is dominant? Or what if milk for a nighttime feeding originates from daytime expressed milk and the infant is also exposed to light—how do these factors synergize? Understanding such interactions will inform early prevention and intervention programs on modifiable factors that influence circadian system maturation, which could be cost effective and easily implemented. Based upon the above reviewed literature and the importance of the circadian system for health and development, future work should focus on the extent to which conflicting time cues influence early clock development and propose evidence-based parental care habits that will strengthen the daily environmental synchronization of the developing human.

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SDW contributed to the research, writing, and editing of this manuscript. MKL, RLS, KPW, CV, and LMH contributed to the editing of this manuscript. All authors read and approved the final manuscript.

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