The neuroendocrine control of the circadian system: adolescent chronotype

Abstract

Scientists, public health and school officials are paying growing attention to the mechanism underlying the delayed sleep patterns common in human adolescents. Data suggest that a propensity towards evening chronotype develops during puberty, and may be caused by developmental alterations in internal daily timekeeping. New support for this theory has emerged from recent studies which show that pubertal changes in chronotype occur in many laboratory species similar to human adolescents. Using these species as models, we find that pubertal changes in chronotype differ by sex, are internally generated, and driven by reproductive hormones. These chronotype changes are accompanied by alterations in the fundamental properties of the circadian timekeeping system, including endogenous rhythm period and sensitivity to environmental time cues. After comparing the developmental progression of chronotype in different species, we propose a theory regarding the ecological relevance of adolescent chronotype, and provide suggestions for improving the sleep of human adolescents.

Figure 1. The Timing of Sleep Delays During Adolescence

This figure was created by averaging data from 13 studies in 9 countries reported in a recent metanalysis of adolescent sleep patterns [62]. The average bed times (black line) and wake times (grey line) are shown for both weekdays (left graph) and weekends (right graph). In general, the timing of sleep becomes progressively later (y-axis = clock time in military hrs) over the course of puberty and adolescence (x-axis=age in years). Note that this change is most striking during weekends, when wake times are relatively unconstrained. On weekdays, when wake times are restricted due to school or work, bedtimes still grow later during adolescence so that total sleep time becomes increasingly restricted (total sleep time is indicated by color, with a key at the top of the figure). Adolescents are recommended to obtain 9-10 hrs of sleep each night, thus anything shown in red (7-7.99 hrs of sleep) can be considered to be severely sleep-restricted.

Figure 2. A Comparison of Chronotype Changes During Puberty in Four Well-Studied Species

Data from males and females are shown in blue and pink, respectively. Chronotype was approximated from the phase variables measured in each experiment [60, 66, 67, 160] and is depicted in terms of relative change in hours. For example, panel C summarizes the results from a study in which pubertal rats showed approximately a 3-4 hr phase advance in multiple phase markers (e.g., peak activity, activity offset [66]). However, as these markers occurred at different hours of the day, what is graphed is a relative phase advance across puberty in general. Pubertal stage was assigned with respect to secondary sex development in the same manner as discussed in [70]. Note that all four species exhibit a shift in chronotype between pre-puberty and puberty, with the two primate species (humans and macaques) exhibiting a phase-delay, and the two rodent species (degus and rats) exhibiting a phase-advance. In general, males show a larger shift during puberty than females. Following maturation, humans (and potentially macaques) exhibit a reversal of this shift, with chronotype growing progressively earlier.

Figure 3. An Illustration of Commonly-Used Circadian Terminology

Depicted on top is a simple sinusoidal model of a subject’s behavioral or physiological rhythm (e.g., daily activity), and depicted below is the environmental cycle to which the subject was exposed (e.g., a light-dark cycle).

Figure 4. Reproductive Cycles Affect Daily Rest/Activity Rhythms

In many rodent species, females show large changes in their rest/activity rhythms over the course of their reproductive cycle. Following elevated estrogen, on the day of estrus females exhibit increased activity and begin their activity earlier in the day (phase-advance). Shown are two examples of estrus-typical wheel-running activity from a degu, with the putative day of estrus marked with an “E.” The activity is graphed as an actogram, with each horizontal line sequentially representing a day of activity (# wheel turns/10 min bin) and the environmental light-dark cycle indicated by the bar at the top of the figure. The red line in the middle of the actogram represents a one-week break in recording, and the estrous cycle length for the female is noted at the bottom [108].

Figure 5. Growing Evidence Suggests That Reproductive Hormones Influence the Functioning of the Circadian System in Adult Rodents

Color is used to indicate whether a property of the circadian system is known to be modulated by hormone exposure (blue=androgen sensitive; red=estrogen sensitive; purple=sensitive to both androgens and estrogens). Depicted are several major input structures to the suprachiasmatic nucleus (SCN), SCN properties, and output structures that are known to be hormone sensitive (vSPZ = ventral subparaventricular zone, CEA=central amygdala, BNST= oval nucleus of the bed nucleus of the stria terminalis, BLA= basolateral amygdala, DG= dentate gyrus). Please note that that we do not mean to imply that all output rhythms directly derive from pathways traversing the local brain oscillators depicted, nor that these structures receive output directly from the SCN. Finally, on the far right, hormonal effects on circadian output rhythm properties are summarized.

Figure 6. Does the Adolescent Shift in Chronotype Represent A Temporal Social Niche?

The shift in chronotype observed during puberty in rodent species resembles shifts seen in other species related to development and dominance status. On the left is depicted the shift in chronotype seen in laboratory rodents, with the percent of daily activity occurring during each time bin plotted relative to time of day (24 hrs). Time of day is divided into four 6 hr bins, and is presented in terms of the typical active period for adult males of the species (green), with the central 12 hours representing nighttime for the nocturnal rat and daytime for the diurnal degu. Prepubertal animals and castrates (red) are more crepuscular, and have more of their activity occur at the end of the active period [66, 67], when they are less likely to have to compete for resources with adult males. On the right are other examples of younger, weaker, or subordinate individuals maintaining activity at a less preferred time of day (red). Each plot again shows a 24 hr day, divided into four 6 hr bins and centered around the typical active period for the larger or more aggressive/dominant individuals in the species (green). The y-axis depicts the relative amount of time spent engaging in activity (in some graphs this is feeding activity, in others general activity) (chub: [106], trout: [6], toads: [57], bellbirds: [42], rats: [92], but also see [25] for more naturalistic examples).