The Role of the Melatoninergic System in Circadian and Seasonal Rhythms-Insights From Different Mouse Strains

Abstract

The melatoninergic system comprises the neurohormone melatonin and its molecular targets. The major source of melatonin is the pineal organ where melatonin is rhythmically produced during darkness. In mammals, melatonin biosynthesis is controlled by the central circadian rhythm generator in the suprachiasmatic nucleus (SCN) and photoreceptors in the retina. Melatonin elicits its function principally through two specific receptors called MT1 and MT2. MT1 is highly expressed in the SCN and the hypophysial pars tuberalis (PT), an important interface for control of seasonal functions. The expression of the MT2 is more widespread. The role of the melatoninergic system in the control of seasonal functions, such as reproduction, has been known for more than 4 decades, but investigations on its impact on the circadian system under normal (entrained) conditions started 2 decades later by comparing mouse strains with a fully functional melatoninergic system with mouse strains which either produce insufficient amounts of melatonin or lack the melatonin receptors MT1 and MT2. These studies revealed that an intact melatoninergic system is not required for the generation or maintenance of rhythmic behavior under physiological entrained conditions. As shown by jet lag experiments, the melatoninergic system facilitated faster re-entrainment of locomotor activity accompanied by a more rapid adaptation of the molecular clock work in the SCN. This action depended on MT2. Further studies indicated that the endogenous melatoninergic system stabilizes the locomotor activity under entrained conditions. Notably, these effects of the endogenous melatoninergic system are subtle, suggesting that other signals such as corticosterone or temperature contribute to the synchronization of locomotor activity. Outdoor experiments lasting for a whole year indicate a seasonal plasticity of the chronotype which depends on the melatoninergic system. The comparison between mice with an intact or a compromised melatoninergic system also points toward an impact of this system on sleep, memory and metabolism.

Keywords: activity rhythms; chronobiology; jet lag; melatonin; mouse strains; seasonality.

FIGURE 1

Relationships between the melatoninergic system and the circadian system. The melatoninergic system comprises the neurohormone melatonin and its molecular targets and is closely connected to the circadian system. The core of the circadian system is located in the hypothalamic SCN (red sinus curve) producing a self-sustained endogenous rhythm with a period length of approximately 24 h. This circadian rhythm generated in the SCN is entrained to the ambient light/dark cycle- which varies with time of day or season (see diagrams). Light/dark signals are received by melanopsinergic ganglion cells of the retina and transmitted to the SCN via the retino-hypothalamic tract (blue). The SCN sends efferent projections to the adjoining paraventricular nucleus (shown in orange), which is the main source of descending autonomic projections to the spinal cord. The pineal gland, the major source of the neurohormone melatonin, is controlled by the sympathetic innervation comprising the intermediolateral column of the thoracic spinal cord (dark green) and the superior cervical ganglion (light green). The pineal gland synthesizes and secrets melatonin at night under the control of the SCN. Thus, melatonin represents an output signal of the circadian system. The length of the melatonin signal corresponds with the length of the dark phase (see light/dark diagrams). Via the blood stream, melatonin provides a humoral signal synchronizing various peripheral oscillators (black and white sinus curves) with the day/night rhythm. The main molecular targets of melatonin are the two melatonin receptors: MT1 and MT2, which are located throughout the body and brain. Within the brain, the highest MT-receptor densities are found in the SCN. Thus, melatonin is not only an output signal, but also an input signal to the SCN. The pars tuberalis of the hypophysis (PT, yellow) is another region with high MT-receptor densities. The oscillatory processes in the PT critically depend on the melatonin signal. These oscillations are of importance with respect to the maintenance of seasonal rhythms (after Pfeffer et al., 2018; MT1 structure: Stauch et al., 2019; MT2 structure: Johansson et al., 2019).

FIGURE 2

Overview of the mouse models used to elucidate the role of melatonin and the melatonin receptors (MT1/2). The C57Black/6J (C57Bl) mice are melatonin deficient. C57Bl mice with a targeted deletion of the MT1 gene (C57Bl MT1 KO; Liu et al., 1997) were initially used for experiments elucidating the role of externally applied melatonin. C3H/HeN (C3H) mice are melatonin-proficient, but visually blind. C3H mice with a targeted deletion of the MT1 receptor (C3H MT1 KO) or the MT2 receptor (C3H MT2 KO) were obtained by breeding the initial melatonin receptor KO mice (Liu et al., 1997; Jin et al., 2003) on a melatonin-proficient C3H/HeN background for at least 10 generations. C3H double melatonin receptor deficient mice (C3H MT1/2 KO) were obtained by crossing C3H MT1 KO and C3H MT2 KO mice and breeding the MT1/2 KO offspring for at least 10 generations. These animals are used to investigate the role of endogenous melatonin and the role of the melatonin receptors (C3H and C57Bl mouse: Jax.org).

FIGURE 3

Seasonal fluctuation of the chronotype and the rhythm stability. Analyses of seasonal fluctuations of the daily chronotype and the rhythm stability of a C3H (upper graphs) and a C57Bl mouse (lower graphs) under semi-natural conditions for 1 year. The daily measurements are shown as grey lines, the blue lines indicate the rolling average over 30 days. The data are blotted against the yearly mean. The melatonin-proficient C3H mouse show a clear seasonal difference in the chronotype with a later, more stable chronotype in summer and an earlier, less stable chronotype in winter. The melatonin-deficient C57Bl mice did not show pronounced seasonal changes in the chronotype and has variable stable and unstable periods.