A research team led by Nagoya University in Japan has found a new neural pathway that links the circadian clock, stress, and alertness in mammals. The team identified a neuron, called the corticotropin-releasing factor (CRF) neuron, which becomes too active when the mammal is under stress, which could trigger insomnia and other sleep disorders. Their findings were recently published in the journal Science Advances.
Living organisms exhibit a 24-hour oscillation called circadian rhythm. In mammals, the central circadian clock, located in the brain’s suprachiasmatic nucleus (SCN) neurons, regulates the sleep-wake cycle. However, in the event of life-threatening situations, the circadian rhythm signal is shut off to keep the animal awake so that it can escape danger even when it would normally be sleep time. Although closing the sleep-wake cycle is necessary for survival, excessive or prolonged stress caused by such dangers can trigger insomnia and other sleep disorders.
It is well known that the circadian clock and stress have an effect on sleep, but it was unclear which neural pathway is essential for sleep regulation and alertness. “
Daisuke Ono, Environmental Medicine Research Institute, Nagoya University
To determine the path, the Nagoya University research team led by Professor Akihiro Yamanaka and Dr. Ono, in collaboration with Takashi Sugiyama at Olympus Corporation in Japan, a study using mice.
The researchers focused on CRF neurons – known to play a role in response to stress – located in the paraventricular nucleus of the hypothalamus. They investigated how sleep and alertness in mice would be affected when the CRF neurons were activated. The results showed that activated CRF neurons keep the animals awake and make them move around energetically, indicating that they are alert. The researchers also observed that CRF neurons remained active when the mice were awake, and when the activity of the neurons was inhibited, the animals’ wakefulness and locomotor activities were reduced.
Further investigations also showed that inhibitory neurons in the SCN, called GABAergic neurons, play a significant role in regulating the activity of CRF neurons, and that activation of CRF neurons stimulates orexin neurons in the lateral hypothalamus, leading to the promotion of wrath.
The team therefore concluded that GABAergic neurons in the SCN control the activity of CRF neurons, which ultimately regulates the sleep-wake cycle. “We identified this neural pathway in mice, which are nocturnal animals. Further studies are needed to clarify how the nocturnal and diurnal difference is regulated in the brain,” said Dr. Ono.
“In today’s society, sleep disorders are a serious problem. We hope that our finding will contribute to the development of new therapies for insomnia and other sleep disorders caused by stress or a disturbed circadian rhythm.”
Ono, D., et al. (2020) The mammalian circadian heart regulator regulates alertness through CRF neurons in the paraventricular nucleus of the hypothalamus. Science Advances. doi.org/10.1126/sciadv.abd0384.