Role of Endogenous Melatonin on the Regulation of Circadian Reentrainment, and Melatonin Receptors and Clock Gene Expression in C57BL/6J Mice
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Melatonin is synthesized primarily in the pineal gland via the enzymes arylalkylamine N-acetyltransferase (AA-NAT) and hydroxyl-indole O-methyltransferase (HIOMT). The synthesis and release follows a circadian rhythm with high levels at night, and low levels during the day. This rhythm is driven by the suprachiasmatic nucleus (SCN), the biological master clock, and is entrained to the environmental light/dark cycle. Melatonin provides time cues to target tissues expressing melatonin receptors (Dubocovich et al., 2010). However, the role of endogenous melatonin in modulating physiological functions in mammals is not well understood. The goal of this study was to assess the role of endogenous melatonin on the regulation of circadian reentrainment and expression of melatonin receptors. We used a colony of melatonin-proficient [ Aanat (+/+); Hiomt (+/+)] (AH+/+) and melatonin-deficient [ Aanat (-/-); Hiomt (-/-)] (AH-/-) congenic C57BL/6J mice (developed by Dr. Takaoki Kasahara lab, RIKEN Brain Science Institute, Japan). We first characterized the mice model finding that: AH+/+ mice displayed a higher level of melatonin content compared to AH-/- mice in the pineal gland and plasma; the spontaneous home cage profile of 15 behaviors in the AH-/- and AH+/+ mice displayed a similar phenotype suggesting a similar genetic background; quantitative receptor autoradiography demonstrated 2-[ 125 I]-iodomelatonin binding sites in the suprachiasmatic nucleus (SCN), paraventricular nucleus of thalamus (PVN) and pars tuberalis (PT) in AH-/- and AH+/+ mouse brain. There was similar expression of 2-[ 125 I]-iodomelatonin binding density in the SCN, with the density being higher at ZT23 versus ZT10 (Zeitgeber Time). AH+/+ mice showed a significant increase in the amplitude of spontaneous running wheel activity compared to AH-/- mice. The reentrainment rate of running wheel activity onset of AH+/+ mice after a 6-hour phase advance of light/dark (LD) cycle was faster than that of AH-/- mice. Under these conditions expression levels of the clock gene m Per1 in the SCN was similar in both genotypes (4 th day postshift). In a 12-hour shift of the LD cycle, AH+/+ mice had a similar reentrainment rate of running wheel activity onset as AH-/- mice. Taken together we conclude that endogenous melatonin appears to increase spontaneous running wheel activity and facilitate circadian reentrainment to a 6-hour dark onset shift, but does not affect melatonin receptor expression in the SCN of C57BL/6J mice.