Circadian rhythms are natural cycles that last approximately 24 hours, governing various biological processes like sleep and wakefulness. A research group from Nagoya University in Japan has recently revealed that neural networks and an intracellular molecule called cyclic adenosine monophosphate (cAMP) play a vital role in regulating these rhythms. This discovery could pave the way for new strategies to treat sleep disorders and other conditions affected by circadian rhythm disruptions. The study was published in Science Advances.
In living organisms, nearly every cell contains a biological clock that controls circadian rhythms. In mammals, the master clock is a group of neurons called the suprachiasmatic nucleus (SCN) in the hypothalamus. It synchronizes the biological clocks in peripheral tissues.
Clock genes encode proteins that regulate daily cycles and are responsible for regulating circadian rhythms through transcription and translation mechanisms. However, some scientists suggest that second messengers, like cAMP and calcium ions, are also involved in SCN’s circadian rhythm regulation. Second messengers are molecules within cells that relay signals from extracellular molecules, impacting cell activity.
Dr. Daisuke Ono, the study’s lead author, said, “The functional roles of second messengers in the SCN remain largely unclear. Among them, cAMP is known to be particularly important in various biological functions. Therefore, understanding its roles in the SCN may lead to new strategies for treating sleep disorders and other health issues caused by circadian rhythm disruption.”
To investigate this, the Nagoya University research team, led by Dr. Ono and collaborating with Yulong Li from Peking University and Takashi Sugiyama from Evident Corporation, studied cAMP in the SCN.
They visualized the circadian rhythm patterns of cAMP and calcium ions using bioluminescent cAMP probes they developed. Blocking the function of a neural network resulted in the loss of cAMP rhythm, while the calcium ion rhythm persisted. This suggests that in the SCN, the neural network controls cAMP rhythm, while calcium ion rhythm is regulated by intracellular mechanisms.
The researchers then focused on vasoactive intestinal peptide (VIP), an extracellular signaling molecule known to modulate cAMP in the SCN. By inhibiting VIP signaling, they observed a loss of cAMP rhythm, indicating that intracellular cAMP rhythms are regulated by VIP in the SCN. They confirmed the presence of a circadian rhythm in VIP release by using a GRAB VIP sensor with green fluorescent protein and found that this rhythm depended on neuronal activity.
To understand how cAMP affects the rhythm of clock genes’ transcription and translation, they conducted experiments using mice. They manipulated cAMP using blue light, which changed the circadian rhythm of the clock gene Per2. Manipulating cAMP rhythm in living mice also shifted their behavioral rhythms. This suggests that intracellular cAMP affects both molecular and behavioral circadian rhythms involving clock genes.
Ono explained, “We concluded that intracellular cAMP rhythms in the SCN are regulated by VIP-dependent neural networks. Furthermore, the network-driven cAMP rhythm coordinates circadian molecular rhythms in the SCN as well as behavioral rhythms. In the future, we would like to elucidate the ancestral circadian clock, which is independent of clock genes and exists universally in life.”