4 | DISCUSSION
The extension of the activity period in WT by chronic caffeine treatment continued for at least 3 weeks after caffeine removal. This means that temporal caffeine exposure brought about extension of period of the biological clock. Chronic MAP treatment extended the circadian activity period and induced activity rhythms with approximately 30 h period in wild-type Balb/c mice (Masubuchi et al., 2001). Data obtained from this study show that after MAP withdrawal, the activity period was significantly longer than that before MAP (23.8±0.0 h vs 23.4±0.071 h, n=4, P=0.001). Period extensions after chronic caffeine or MAP administration suggest their similar effects on the circadian period. After-effect is long lasting circadian period change after exposure to various environmental lights (Pittendrigh & Daan, 1976). We showed that PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1) is involved in after-effect of activity rhythm by light induced phase shift (Masubuchi et al., 2010). Although the mechanism of after-effect is not well known, it is possible that a common mechanism drives after-effect by light and after-effect by non-photic intervention, that is, the period extension after temporal caffeine treatment.
Activity rhythm generation by chronic caffeine administration in CryDKO supports the idea that caffeine acts as an inhibitor of adenosine at A1AR/D1R and A2AAR/D2R heteromers and acts similarly to the dopamine increase in the synaptic cleft by MAP. D1R, D2R, and A2AAR are strongly expressed in the striatum, whereas A1AR is widely expressed in the brain (Fuxe et al., 2010; Mishra et al., 2018). If MAP- and caffeine-induced rhythms are driven by a common system that acts through A1AR/D1R and/or A2AAR/D2R, it may also involve the striatum.
Caffeine induced activity rhythms with various periods, including circasemidian and circadian rhythms, and longer periods in CryDKO. In addition to circadian rhythm, rhythms with a period longer or shorter than 24 h have been hypothesized in human physiology. Internal desynchronization of biological rhythms is known under isolated constant condition. The period of the sleep-wake rhythm becomes either much longer or shorter than 24 h, whereas the period of the body temperature rhythm remains close to 24 h (Aschoff et al., 1967; Wever, 1979). Dissociation of two oscillators, a circadian oscillator and an oscillator with a period longer or shorter than 24 h, is considered to cause internal desynchronization. Analyzing caffeine-induced rhythms with longer and shorter periods than 24 h may be important for clarifying the mechanism of internal desynchronization.
The caffeine-induced rhythms spontaneously changed over time. Interestingly, the long period in CryDKO#07 (29.25 h, Figure 3a) and #10 (28.33 h, Figure 3b) quickly became approximately half the (circasemidian) period (13.33 h, 17.16 h) and returned to a long period (30.00 h, 30.91 h). In humans, sleep propensity increases not only at night, but also in the afternoon. 2 per day sleep/wake regulation is thought to cause afternoon sleepiness and nap. The harmonics of circadian oscillators, circadian oscillator splitting into 2 antiphase circadian oscillators, model, and the independent circasemidian oscillator model are hypothesized to cause 2 per day regulation. The former does not account for the fact that naps are often skipped (Broughton & Mullington, 1992). The short-term appearance and disappearance of the circasemidian rhythm, as observed in CryDKO#07 and #10, may account for the skipping of naps and variable afternoon sleepiness.
Caffeine is the most consumed psychoactive drug in the world (Ferré, 2016). Caffeine at bedtime has significant effects on sleep disturbance (Drake et al., 2013). However, rhythm induction by caffeine provides a possibility that caffeine is useful not only to increase wakefulness but also to control the sleep-wake rhythm.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTIONS
SM designed research. SM, TY, and KK performed experiments. KI, TT, and WN contributed new reagents/analytic tools. SM wrote the manuscript. TY, KK, KI, TT, and WN reviewed the manuscript.
CONSENT FOR PUBLICATION
The authors consent to the publication of this manuscript.
DATA AVAILABILITY STATEMENT
All data and materials are available for review
ORCID
Satoru Masubuchihttps://orcid.org/0000-0003-0377-088X
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