An examination of the relationship between melatonin and circadian rhythms: impact on reproduction, rhythmic behaviors and growth

Melatonin, a hormone secreted in the brain at night, is thought to be involved in the regulation of the biological clock and photoperiodicity. However, the function of melatonin is not well understood because laboratory mice have lost the ability to synthesize melatonin owing to the rearing environment that they have been kept in for a long time.

An international collaborative research group led by Senior Researcher Takaoki Kasahara of the Center for Brain Science, Development Researcher Tamio Furuse of the BioResource Research Center, and Development Engineer Ikuo Miura at RIKEN, as well as Professor Margarita Dubocovich of the Faculty of Medicine and Biomedical Sciences at the University of Buffalo, State University of New York, Chief Professor Tadafumi Kato of the Graduate School of Medicine at Juntendo University, and others developed laboratory mice capable of synthesizing melatonin and revealed that melatonin is involved in the elimination of jet lag and daily torpor in mammals. These findings were published in the Journal of Pineal Research.

Numerous studies have reported the effects of melatonin administration in humans and mice. In Japan, melatonin agents, approved in 2020, are covered by insurance for "difficulty falling asleep owing to neurodevelopmental disorders in childhood." In addition, a variety of supplements containing melatonin are sold at drug stores in the United States and other countries. However, the hormonal function of melatonin is not well understood in mice, which are typical experimental animals. This is because they have lost the ability to synthesize melatonin after being bred in laboratory conditions for more than 120 years.

Thus, the research group focused on the MSM/Ms mice capable of synthesizing melatonin, which were produced approximately 40 years ago and possess various properties of wild mice. The MSM/Ms lineage of mice were crossed with the lineage C57BL/6J mice, which are a common laboratory mouse line incapable of synthesizing melatonin, and the offspring were crossed again with C57BL/6J mice. This was repeated more than 10 times to finally establish the congenic mouse line capable of synthesizing melatonin, as well as the one incapable of synthesizing melatonin. Although the congenic mice capable of synthesizing melatonin synthesized and secreted a large amount of melatonin at night, there was no difference in the expression level and distribution of melatonin receptors in the brain between the congenic mice capable and incapable of synthesizing melatonin.

Next, they examined the activity rhythm, lifespan, body weight, gonad weight, and reproductive efficiency, and emotional and social behaviors of both lines of congenic mice under various light conditions. The results showed that mice capable of synthesizing melatonin eliminated jet lag quickly and gained body weight rapidly. In contrast, mice incapable of synthesizing melatonin were found to have large gonads and high reproductive efficiency. In addition, the examination of daily torpor in situations that mimic food shortages showed that the ability to synthesize melatonin resulted in a deep and long daily torpor and suppressed weight loss.

Senior Researcher Kasahara says, "Melatonin synthesis efficiently suppresses energy consumption when food is scarce, so we speculate that negative natural selection acts on melatonin synthesis in wild mice. In addition, mice show rapid growth and high reproductive efficiency in the absence of the ability to synthesize melatonin. Therefore, positive natural selection may have acted in the mice kept in the rearing house."

Mice incapable of synthesizing melatonin have been used in experiments, even in research on biological clocks and sleep. With the wide use of the congenic mice capable of synthesizing melatonin developed in this study, new developments in research can be expected in the future.

Professor Margarita says, "Using this mouse line, we hope to proceed with research on the circadian rhythm that we have not been able to examine in detail. We may also be able to obtain interesting results on the role of melatonin in the retina."