The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24 hr period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period (Per) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown. Our study in mice demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA)-calcium/calmodulin-dependent kinase (CaMK)-cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.
Keywords: clock genes; environmental signal; jet lag; kinases; light adaptation; mouse; neuroscience; shift work.
Our bodies evolved to follow daily rhythms, influencing our sleeping and waking patterns and our usual mealtimes. These rhythms are based on circadian clocks that allow our bodies to stay in tune with the day-night cycle in our environment. Circadian rhythms are controlled by a set of biological mechanisms termed molecular clocks, which are found in every cell and organ. The body also has a ‘master clock’, which is in a part of the brain called the suprachiasmatic nuclei (SCN). The SCN is the body’s main ‘timekeeper’ and coordinates all our daily cycles of biological processes and behaviours. Molecular clocks also respond to artificial stimuli, which can cause shifts in circadian rhythms. These alterations disrupt the normal alignment of our bodily processes with the environmental day-night cycle, meaning that our bodies work less efficiently. For example, light exposure early during the night changes our circadian rhythms so that we go to sleep and wake up later, a phenomenon called phase delay. The enzyme CDK5 is part of the SCN’s master clock. CDK5 helps control normal circadian rhythms: it is more active in the dark (i.e., at night), when it helps to turn off genes that respond to light, and is inactive in light conditions, ensuring that the light response genes stay switched on during the day. Since CDK5 is also involved in many neurological diseases linked to disturbed circadian rhythms, Brenna et al. wanted to determine whether it also controlled the circadian shift caused by light exposure early during the night. To simulate this mistimed light, mice were exposed to 15 minutes of bright light two hours after the onset of darkness in the laboratory light/dark cycle. Biochemical and genetic analysis revealed that in standard mice, this reduced CDK5 activity in the SCN, switched light response genes back on, and resulted in phase delay. However, light exposure did not cause any shift in behaviour in genetically engineered mice lacking CDK5, confirming that CDK5 was indeed responsible for the phase delay observed. These results contribute to our understanding of the mechanisms behind the body’s response to stimuli that force our internal clock out of sync with our environment. Brenna et al. hope that targeting CDK5 may one day help us cope better with circadian misalignment and the health problems associated with it, especially for people affected by jet lag or shift work.
© 2024, Brenna et al.