All animals need to sleep for varying durations and in humans, sleep duration changes over their lifetime, gradually reducing from birth through to old age. The mammalian body appears to use time spent asleep to recover from the effects of daily life, such as removing waste products from the brain and restoring the immune system, and may use the time to process experiences and lay down long-term memories. However, the fundamental reasons for sleep and the mechanisms by which sleep duration is regulated remains largely unknown.  Now, a study from researchers at the University of Tokyo and RIKEN has identified seven genes responsible for causing mice to stay awake or fall asleep based on a theoretical model of sleep and on experiments using 21 different genetically-modified mice, some of which showed different sleep durations. The team state that it is hoped their research will contribute to the understanding and treatment of sleep disorders and associated neurodegenerative diseases.  The opensource study is published in the journal Neuron.

Previous studies show that sleep is one of the most fundamental physiological functions. From flies to humans, it seems that most animals sleep, with the complex dynamics of sleep/wake cycles proposed by a number of computational models.  However, genetic evidence for these mechanisms has been lacking especially in mammals.  The current study uses a variety of scientific techniques, including computational modeling and studying knockout mice, to search for the fundamental mechanism underlying sleep.

The current study developed a computational or in silico model of sleep, which predicted that sleep duration is regulated by calcium and identified multiple genes that were potentially involved. The lab then tested their in silico predictions against 21 different genetically-modified mouse types to reveal a mechanism regulated by calcium ions is indeed responsible for controlling sleep duration.

The group then applied an efficient type of the CRISPR method to remove genes involved in calcium regulation to create 21 genetically-modified mice. By identifying mice with abnormal sleep patterns, the team was able to pinpoint seven genes that are critical for increasing or decreasing sleep duration.  Results show that all seven genes allow calcium-dependent changes in neurons that make them resist becoming active, a process called hyperpolarization. As predicted by the model, data findings show that down-regulating six of these genes reduced sleep duration and down-regulating the final, seventh, gene led to longer bouts of sleep.  The lab conclude that sleep is regulated by calcium-related pathways and inhibiting NMDA-receptors directly evoked neuronal excitation, which contributed to reduced sleep.

The team surmise that their findings should contribute to the understanding and treatment of sleep disorders and the neurologic diseases associated with them.  For the future, the researchers state that in addition to becoming new molecular targets for sleep drugs, the genes identified could also become targets for drugs that treat certain psychiatric disorders that occur with sleep dysfunction.

Source: RIKEN