Summary: Scientists at UC San Francisco have identified a second gene linked to natural short sleep. Through optogenetic stimulation of neurons in the dorsal pons that express ADRB1, they showed these cells promote wakefulness. Mice carrying the ADRB1 mutation were easier to rouse and displayed a shift in the balance between wake-promoting and sleep-promoting neurons, offering a mechanistic explanation for naturally brief, restorative sleep in some people.
Source: UCSF
After more than a decade of research, UC San Francisco investigators who previously discovered the first known human gene tied to “natural short sleep” have now identified a second gene that produces the same trait.
Ying-Hui Fu, PhD, professor of neurology and member of the UCSF Weill Institute for Neurosciences, led the teams that found both genes. Natural short sleep describes individuals who consistently sleep four to six hours per night yet feel fully rested. The new work, published in Neuron, reveals how a mutation in the ADRB1 gene contributes to this rare sleep pattern.
Before these discoveries, many researchers assumed sleep duration was shaped mainly by behavior and environment — alarms, caffeine, medications and other factors that mask a person’s innate need for sleep. Fu and colleagues showed that in at least some cases, inherited gene variants directly determine how long people naturally sleep.
The first genetic link to natural short sleep was discovered in 2009 when Fu’s team reported that carriers of a mutation in the DEC2 gene averaged roughly 6.25 hours of sleep per night versus 8.06 hours for noncarriers. That finding established a genetic basis for short sleep in some families, but the DEC2 mutation is rare and could not explain all naturally short sleepers.
In the new study, the researchers examined a family spanning three generations in which multiple members were natural short sleepers but did not carry the DEC2 mutation. Using whole-genome sequencing combined with linkage analysis to narrow the chromosomal region associated with the trait, they identified a single-letter change in ADRB1, the gene that encodes the beta-1 adrenergic receptor, as being associated with short sleep in this family.
To understand how this ADRB1 mutation might alter sleep, the team carried out experiments in cultured cells and engineered mice carrying the same mutation in the mouse gene. In cell models, the mutant beta-1 adrenergic receptor was less stable and degraded more quickly than the normal protein, indicating altered receptor dynamics and signaling.
In mice, ADRB1 was found to be highly expressed in the dorsal pons, a brainstem region known to participate in sleep-wake regulation. The researchers used optogenetics — a method that enables precise activation of genetically targeted neurons with light — to stimulate ADRB1-expressing neurons in the dorsal pons. Activating these neurons immediately woke mice from non-REM sleep, demonstrating that this population promotes arousal.
Further analysis showed that in mice carrying the ADRB1 mutation, those wake-promoting neurons were more easily activated. The mutant animals also showed a noticeable shift in the ratio of wake-promoting to sleep-promoting neurons in the dorsal pons, favoring wakefulness. Together, the data suggest the mutant ADRB1 allele produces neural circuitry that is easier to arouse and maintains wakefulness longer, providing a biological explanation for naturally brief and restorative sleep in carriers.
Importantly, carriers of natural short sleep variants do not show the negative health consequences typical of chronic sleep deprivation. Fu notes that while many people are chronically short on sleep relative to their needs — increasing risks for cardiovascular disease, metabolic disorders, dementia and other conditions — natural short sleepers do not suffer those adverse effects. Instead, some studies report they tend to be more energetic, more optimistic, better at multitasking, less prone to jet lag, and in some reports may enjoy a higher pain threshold and even increased longevity. The biological mechanisms behind these advantages remain under investigation.
Fu and co-senior author Louis Ptáček, MD, the John C. Coleman Distinguished Professor in Neurodegenerative Diseases, emphasize that sleep regulation is complex and likely involves multiple genes and brain regions. The identification of ADRB1 as a second short-sleep gene supports the idea that a network of genetic and neural factors determines individual sleep needs and quality.
By studying naturally short sleepers and the neural circuits affected by these rare mutations, researchers aim to uncover what constitutes efficient, healthy sleep. Insights from these families and animal models may ultimately inform strategies to improve sleep quality for the broader population and reduce the health burdens associated with chronic poor sleep.
Authors: Additional contributors to the study include Guangsen Shi, Lijuan Xing, David Wu, Bula J. Bhattacharyya, Thomas McMahon, S.Y. Christin Chong and Andrew Krystal of UCSF; Christopher R. Jones of the University of Utah; and Jason A. Chen, Giovanni Coppola and Daniel Geschwind of UCLA.
Funding: The research was supported by the NINDS Informatics Center for Neurogenetics and Neurogenomics (grant P30 NS062691), several NIH grants (NS099333, NS072360, NS104782 and P30 DK063720) and the William Bowes Neurogenetics Fund.
Disclosures: The authors report no competing interests.
Source:
UCSF
Media Contacts:
Jason Alvarez – UCSF
Image Source:
The image is in the public domain.
Original Research: Open access — “A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors” by Ying-Hui Fu et al., published in Neuron. DOI: 10.1016/j.neuron.2019.07.026
Abstract
A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors
Highlights
• A mutation in ADRB1 leads to a natural short sleep trait in humans
• Mice engineered with the same mutation display similar short-sleep behavior
• Activity of dorsal pons ADRB1-positive neurons is associated with REM sleep and wakefulness
• The mutation increases the population activity of dorsal pons ADRB1-positive neurons
Summary
Sleep is essential to health, and many diseases are linked to long-term poor sleep quality. To harness sleep as a means to improve health and treat sleep-related disorders, a deeper understanding of sleep regulation is needed. This study identifies a rare mutation in the β1-adrenergic receptor gene in humans who require fewer hours of sleep. In cultured cells, the mutation reduces receptor stability and dampens signaling. Mice carrying the mutation exhibit short-sleep behavior, and ADRB1-expressing neurons in the dorsal pons are active during REM sleep and wakefulness. Experimental activation of these neurons induces wakefulness, and the mutation alters their activity. These findings underscore the important role of β1-adrenergic receptors in sleep/wake regulation.