Impact of Aging on Diurnal Expression Patterns of CLOCK and BMAL1 in the Mouse Brain

Mammalian circadian rhythms are generated by a network of transcriptional and translational loops in the expression of a panel of clock genes in various brain and peripheral sites. Many of the output rhythms controlled by this system are significantly affected by ageing, although the mechanisms of age-related circadian dysfunction remain opaque. The aim of this study was to investigate the effect of aging on the daily oscillation of two clock gene proteins (CLOCK, BMAL1) in the mouse brain. Clock gene protein expression in the brain was measured by means of immunohistochemistry in groups of young (4 months) and older (16 months) mice sampled every 4h over a 24-h cycle. CLOCK and BMAL1 were constitutively expressed in the suprachiasmatic nucleus (SCN; the master circadian pacemaker) in young adult animals. We report novel rhythmic expression of CLOCK and BMAL1 in a number of extra-SCN sites in the young mouse brain, including the hippocampus, amygdala and the paraventricular, arcuate and dorsomedial nuclei of the hypothalamus. Aging altered the amplitude and/or phase of expression in these regions. These results indicate hitherto unreported expression patterns of CLOCK and BMAL1 in non-SCN brain circadian oscillators, and suggest that alterations of these patterns may contribute to age-related circadian dysfunction.