Researchers studied the DNA of several members from a family who function normally on 6 hours of sleep, which is significantly less than average. After conducting genetic linkage studies and whole-exome sequencing, the very rare variant ADRB1, which is a mutation of the ß1-adrenergic receptor gene, was shown to impact sleep and wakefulness regulation. By activating these ADRB1 neurons, individuals will have heightened wakefulness, which this mutation concurrently causes.

One of the 2 senior study authors, Louis Ptáček, MD, professor in the department of neurology at the University of California, San Francisco (UCSF) Weill Institute for Neurosciences, highlighted the study’s focus on the relatively unknown influence that neurons contribute to sleep regulation.

“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” said Ptáček. “This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”

Researchers first studied the protein of the gene variant in vitro to determine whether this mutation has functional consequences. After comparing the mutant gene with wild-type protein in cultured cells, ADRB1 was revealed as less stable due to decreased protein stability and dampened signaling in response to agonist treatment. These factors were shown through the alteration of the ß1-adrenergic receptor’s function, which hinted at its likely functional consequences in the brain.

Studies were then conducted in vivo in which researchers administered the mutation in mice to examine if it had any influence on sleep-related behaviors. Compared with regular mice, the mutated mice slept on average 55 minutes less. Additional analysis of the mutation revealed its heightened levels in the dorsal pons, which is a part of the brain stem involved in subconscious activities like respiration, eye movement, and sleep. Shorter amounts of non—rapid eye movement (REM) sleep (53 minutes less) and REM sleep (7 minutes less) in mutated mice were 2 key indicators of its chief influence compared with regular mice.

“These results indicated that the Adrb1 A187V mutation can lead to short sleep and increased mobile time, similar to what we observe in the human subjects,” said the authors. The correlation of ADRB1’s impact on mice and humans show a significant alteration in sleep necessity. “Sleep is one of the most important things we do,” said senior study author Ying-Hui Fu, PhD, professor of neurology at the UCSF Weill Institute for Neurosciences.

Fu indicated that further research on sleep and wakefulness regulation may contribute to developing new drugs that can benefit healthcare. “Not getting enough sleep is linked to an increase in the incidence of many conditions, including cancer, autoimmune disorders, cardiovascular disease, and Alzheimer’s,” said Fu.

Researchers plan to next study other families for additional genes correlated to sleep and the function of ADRB1 protein in other parts of the brain.

Reference

Shi G, Xing L, Wu D, et al. A rare mutation of ß1-adrenergic receptor affects sleep/wake behaviors [published online August 28, 2019]. Neuron. doi: 10.1016/j.neuron.2019.07.026.