Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex

Abstract

The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum, as revealed by immunohistochemistry. These findings give reason to further pursue the physiological significance of circadian oscillators in the mouse neocortex and cerebellum.

The Sleeping Cerebellum

“…Genes that regulate the rhythmicity of neurons in the SCN are called clock genes. Several clock genes, including Arntl, Nr1d1, Bmal1, Per1, Per2, and Cry1, have also been found in the Purkinje cell and granular cell layer of the cerebellum [132,133]. Their expression pattern follows that of the SCN, but with a delay of 5 h [132,134].…”

“…Several clock genes, including Arntl, Nr1d1, Bmal1, Per1, Per2, and Cry1, have also been found in the Purkinje cell and granular cell layer of the cerebellum [132,133]. Their expression pattern follows that of the SCN, but with a delay of 5 h [132,134]. Even in vitro the cerebellum is able to express near-24-h rhythms and these rhythms can be shifted by shifting 'mealtime' exposure [135].…”

Processing of sub- and supra-second intervals in the primate brain results from the calibration of neuronal oscillators via sensory, motor, and feedback processes

“…In contrast to a much longer (24 h) circadian rhythm, which relies on the rhythmic expression of a set of clock genes with specific daily profiles in the suprachiasmatic nucleus and other parts of the brain (Rath et al, 2014), the interval timing in the sub-to supra-second range mainly relies on neuronal mechanisms. To understand the mechanisms underlying the neuronal clocks, one should first look at the mechanisms of the mechanical and electronic clocks.…”

Transcranial Light Alters Melanopsin and Monoamine Production in Mouse (Mus musculus) Brain

“…Whether light has a direct effect on its expression in the cerebellum has not yet been clarified. It has also been shown that the cerebellum is involved in maintaining the circadian rhythm in rodents through clock gene regulation [53,54], and OPN4 resets the circadian clock through the activation of clock gene Per1 [55]. Therefore, we must consider the possibility that OPN4 may affect the circadian rhythm through clock gene activation in the cerebellum.…”