Loss of circadian rhythm and light‐induced suppression of pineal melatonin levels in Cry1 and Cry2 double‐deficient mice

Abstract

Cryptochrome 1 and 2 (Cry1 and Cry2) are considered essential for generating circadian rhythms in mammals. The role of Cry1 and Cry2 in circadian rhythm expression and acute lightinduced suppression of pineal melatonin was assessed using Cry1 and Cry2 double-deficient mice (Cry1 ) ⁄ ) /Cry2 ) ⁄ ) ) developed from the C3H strain that synthesizes melatonin. We examined the circadian variation of pineal melatonin under a 12:12-h light-dark (LD) cycle and constant darkness (DD). Light suppression of pineal melatonin concentration was analyzed by subjecting a 30-min light pulse at the peak phase of melatonin concentration. Wild-type mice showed significant rhythmicity in pineal melatonin concentration with the highest level at Zeitgeber time 22 (ZT22, where time of light on was defined as ZT0) under LD or ZT18 on the first day of DD. In contrast, Cry1 ) ⁄ ) /Cry2 ) ⁄ ) mice did not show significant circadian rhythmicity, with only a small peak observed at ZT22 in LD. Nevertheless, a significant daily variation could be observed under DD, with a small increase at ZT6 and ZT18 h. Melatonin concentration was significantly suppressed by acute light pulse at ZT22 in wild-type mice but not in Cry1 ) ⁄ ) /Cry2 ) ⁄ ) mice. The present results suggest that Cry genes are required for regulating pineal melatonin synthesis via circadian and photic signals from the suprachiasmatic nucleus of the hypothalamus (SCN).

Interactions between endocrine and circadian systems

“…PER1 deficiency has been shown to enhance Aanat transcription, enzymatic activity and hence melatonin secretion (Chen & Baler 2000, Christ et al 2010. In CRY1/2 double-deficient mice on a melatonin-proficient genetic background not only is the melatonin rhythm blunted under light-dark conditions, but also photic suppression of melatonin is abolished (Yamanaka et al 2010). Together, these data suggest that clock genes impinge on pineal melatonin rhythmicity.…”

The Diurnal Oscillation of MAP (Mitogen-Activated Protein) Kinase and Adenylyl Cyclase Activities in the Hippocampus Depends on the Suprachiasmatic Nucleus

“…Even though the SCN does not directly project to the hippocampus, it projects to multiple areas including the septum that innervate hippocampal sub-regions (Watts and Swanson, 1987; Morin et al, 1994). Furthermore, the SCN can indirectly modulate adenylyl cyclase activity during the circadian cycle by controlling the release of melatonin from the pineal gland (Yamanaka et al, 2010). Melatonin receptors in the hippocampus are coupled to inhibition of adenylyl cyclase activity through Gi and suppression of LTP (Wang and Storm, 2005).…”

Circadian regulation of pineal gland rhythmicity

“…Cry1/2 null mice, generated in melatonin-proficient background, do not display circadian rhythms of melatonin secretion under normal light and dark condition and show very weak rhythms in constant darkness (Yamanaka et al, 2010). …”