Researchers from the University of California, Berkeley and Stanford University have investigated the brain circuits that regulate the release of growth hormone during sleep. Their findings reveal new feedback mechanisms that keep growth hormone levels finely tuned. This discovery could lead to advancements in treating individuals with sleep disorders associated with metabolic issues like diabetes, as well as degenerative diseases such as Parkinson’s and Alzheimer’s.
Sleep is known to promote tissue growth and regulate metabolism by partially promoting growth hormone (GH) release, but the underlying circuit mechanism is unknown. Ding et al. show how GH release, which is enhanced in both rapid eye movement (REM) and non-REM (NREM) sleep, is regulated by sleep-wake-dependent activities of distinct hypothalamic neurons that express GH release hormone (GHRH) and somatostatin (SST). Arcuate nuclei SST neurons inhibit GH release by targeting nearby GHRH neurons that stimulate GH release, while periencephalic SST neurons project onto the median ridge to inhibit GH release. GH release is associated with significant surges of both GHRH and SST activity during REM sleep, while NREM sleep sees moderate increases in GHRH and reductions in SST activity. Furthermore, Ding et al. identified negative feedback pathways where GH increases the excitability of locus ceruleus neurons, leading to increased arousal. Image credit: Ding et al, doi: 10.1016/j.cell.2025.05.039.
“We have gained significant insights into this area,” said Xinlu Ding, a postdoctoral researcher at the University of California, Berkeley.
“We directly recorded the neural activity of mice to understand the underlying processes.”
“Our findings provide a foundational circuit to explore various treatment options moving forward.”
Neurons that manage growth hormone release during the sleep-wake cycle—specifically growth hormone-releasing hormone (GHRH) neurons and two types of somatostatin neurons—are located deep within the hypothalamus, an ancient brain region present in all mammals.
Once released, growth hormone enhances the activity of locus coeruleus neurons, a brainstem region involved in arousal, attention, cognition, and curiosity.
Dysregulation of locus coeruleus neurons is linked to numerous psychiatric and neurological disorders.
“Understanding the neural circuits involved in growth hormone release could ultimately lead to new hormone therapies aimed at enhancing sleep quality and restoring normal growth hormone levels,” explained Daniel Silverman from the University of California, Berkeley.
“Several experimental gene therapies have been developed that target specific cell types.”
“This circuit could serve as a new approach to modulate the excitability of the locus coeruleus, which has not been effectively targeted before.”
The researchers investigated neuroendocrine circuits by implanting electrodes into the mouse brain and measuring activity changes triggered by light stimulation of hypothalamic neurons.
Mice have short sleep bouts (lasting several minutes at a time) throughout day and night, providing ample opportunities to study fluctuations in growth hormone during the sleep-wake cycle.
Utilizing advanced circuit mapping techniques, researchers found that the two peptide hormones (GHRH and somatostatin) regulating growth hormone release operate differently during REM and non-REM sleep.
Both somatostatin and GHRH promote growth hormone release during REM sleep; however, somatostatin decreases and GHRH sees only moderate increases during non-REM sleep, which still results in growth hormone release.
Growth hormone release regulates locus coeruleus activity through a feedback mechanism, creating a homeostatic balance.
During sleep, growth hormone accumulates at a gradual pace, stimulating the locus coeruleus and fostering arousal, according to the new findings.
However, excessive activation of the locus coeruleus can paradoxically lead to drowsiness.
“This indicates that sleep and growth hormone form a delicate balance. Insufficient sleep diminishes growth hormone release, while excessive growth hormone may drive the brain toward wakefulness,” Dr. Silverman noted.
“Sleep facilitates growth hormone release, which in turn regulates arousal. This equilibrium is crucial for growth, repair, and metabolic health.”
Growth hormone functions partially through the locus coeruleus, influencing overall brain alertness during wakefulness, emphasizing the importance of maintaining proper balance for cognitive function and attention.
“Growth hormone is pivotal not only for muscle and bone development and reducing fat tissue, but it also offers cognitive benefits and can elevate overall arousal levels upon waking,” stated Dr. Ding.
study Published in the journal Cell.
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Xinlu Ding et al. 2025. Neuroendocrine circuits for sleep-dependent growth hormone release. Cell 188 (18): 4968-4979; doi: 10.1016/j.cell.2025.05.039
Source: www.sci.news
