During sleep, the brain releases growth hormone, which is important for building muscle and bone and reducing fat. Researchers at the University of California, Berkeley have identified the specific brain circuits in mice that regulate this process and discovered a feedback mechanism in the brainstem that promotes wakefulness after restful sleep.

The study, published in Cell, explains why lack of sleep—especially during non-REM sleep—leads to lower levels of growth hormone. The research provides a map for understanding how sleep and hormone regulation are connected. It also suggests possible new ways to treat people with sleep disorders related to metabolic conditions such as diabetes or degenerative diseases like Parkinson’s and Alzheimer’s.

“People know that growth hormone release is tightly related to sleep, but only through drawing blood and checking growth hormone levels during sleep,” said Xinlu Ding, postdoctoral fellow at UC Berkeley’s Department of Neuroscience and the Helen Wills Neuroscience Institute. “We’re actually directly recording neural activity in mice to see what’s going on. We are providing a basic circuit to work on in the future to develop different treatments.”

Growth hormone helps regulate glucose and fat metabolism. Insufficient sleep can increase risks for obesity, diabetes, and cardiovascular disease.

The neurons responsible for releasing growth hormone during the sleep-wake cycle—growth hormone releasing hormone (GHRH) neurons and two types of somatostatin neurons—are located deep within the hypothalamus. Once released, growth hormone increases activity in locus coeruleus neurons in the brainstem, which play a role in arousal, attention, cognition, and novelty seeking. Problems with these neurons have been linked to psychiatric and neurological disorders.

“Understanding the neural circuit for growth hormone release could eventually point toward new hormonal therapies to improve sleep quality or restore normal growth hormone balance,” said Daniel Silverman, UC Berkeley postdoctoral fellow and study co-author. “There are some experimental gene therapies where you target a specific cell type. This circuit could be a novel handle to try to dial back the excitability of the locus coeruleus, which hasn’t been talked about before.”

Researchers led by Yang Dan, professor of neuroscience and molecular and cell biology at UC Berkeley, used electrodes inserted into mouse brains to measure changes after stimulating hypothalamic neurons with light. Mice provided many opportunities for observation because they sleep frequently throughout day and night.

Using advanced circuit tracing methods, researchers found that GHRH promotes growth hormone release while somatostatin inhibits it; both surge during REM sleep but act differently during non-REM phases.

Released growth hormone regulates locus coeruleus activity as part of a feedback loop helping maintain balance between sleepiness and wakefulness. Growth hormone slowly accumulates during sleep until it stimulates wakefulness; overexcitation can paradoxically cause more drowsiness.

“This suggests that sleep and growth hormone form a tightly balanced system: Too little sleep reduces growth hormone release, and too much growth hormone can in turn push the brain toward wakefulness,” Silverman said. “Sleep drives growth hormone release, and growth hormone feeds back to regulate wakefulness, and this balance is essential for growth, repair and metabolic health.”

Ding added: “Growth hormone not only helps you build your muscle and bones and reduce your fat tissue, but may also have cognitive benefits, promoting your overall arousal level when you wake up.”

Funding came from Howard Hughes Medical Institute (HHMI), which previously supported Dan as an HHMI investigator; Dan currently holds the Pivotal Life Sciences Chancellor’s Chair in Neuroscience at UC Berkeley. Other contributors included researchers from Stanford University.