Scientists have long known that growth hormone levels rise during sleep, especially during the deep, non-REM stage. What has remained unclear is exactly how the brain controls this process.

Now, researchers at the University of California, Berkeley have uncovered the brain circuitry responsible for regulating growth hormone during sleep. Their study, published in the journal Cell, also reveals a previously unknown feedback system that helps keep growth hormone levels in balance.

The discovery offers new insight into the close relationship between sleep and hormone regulation. It could eventually guide new treatments for sleep disorders linked to metabolic diseases such as diabetes, as well as neurodegenerative conditions including Parkinson's and Alzheimer's disease.

"People know that growth hormone release is tightly related to sleep, but only through drawing blood and checking growth hormone levels during sleep," said study first author Xinlu Ding, a postdoctoral fellow in 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."

Because growth hormone also helps regulate glucose and fat metabolism, consistently poor sleep may increase the risk of obesity, diabetes, and cardiovascular disease.

How the Brain Controls Growth Hormone During Sleep

The nerve cells that coordinate growth hormone release are located deep within the hypothalamus, an ancient brain region found across mammals. These include growth hormone-releasing hormone (GHRH) neurons, along with two different types of somatostatin neurons.

Once growth hormone is released, it activates neurons in the locus coeruleus, a brainstem region involved in alertness, attention, thinking, and responding to new experiences. Problems affecting the locus coeruleus have been linked to numerous neurological and psychiatric 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, a 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."

Mapping the Sleep Growth Hormone Circuit

Working in the laboratory of Yang Dan, professor of neuroscience and molecular and cell biology at UC Berkeley, the research team studied the brain circuits in mice by placing electrodes in their brains and stimulating hypothalamic neurons with light while recording neural activity.

Mice naturally sleep in short bursts lasting only a few minutes throughout the day and night. That pattern allowed researchers to repeatedly observe changes in growth hormone activity across many sleep and wake cycles.

Using advanced circuit tracing techniques, the team discovered that the two peptide hormones responsible for regulating growth hormone release behave differently depending on the stage of sleep. GHRH promotes growth hormone release, while somatostatin suppresses it.

During REM sleep, both GHRH and somatostatin increase, leading to greater growth hormone release. During non-REM sleep, however, somatostatin levels fall while GHRH rises only moderately, creating a different pattern of hormone regulation.

A Feedback Loop That Balances Sleep and Wakefulness

The researchers also identified a previously unknown feedback mechanism involving the locus coeruleus.

As growth hormone gradually builds up during sleep, it stimulates the locus coeruleus and encourages wakefulness. But if activity in the locus coeruleus becomes too high, it unexpectedly begins promoting sleepiness instead, a finding Silverman reported earlier this year.

"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."

Because growth hormone influences the locus coeruleus, which plays a central role in maintaining alertness during the day, this newly identified system may also affect attention and other aspects of cognitive function.

"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," Ding said.

The research was supported by the Howard Hughes Medical Institute (HHMI), which, until this year, supported Dan as an HHMI investigator, and the Pivotal Life Sciences Chancellor's Chair fund. Dan is the Pivotal Life Sciences Chancellor's Chair in Neuroscience. Additional co-authors include Peng Zhong, Bing Li, Chenyan Ma, Lihui Lu, Grace Jiang, Zhe Zhang, Xiaolin Huang, Xun Tu, and Zhiyu Melissa Tian of UC Berkeley, along with Fuu-Jiun Hwang and Jun Ding of Stanford University.