GH and IGF-1 Shape Brain Health and Drive Neuropsychiatric Disease Risk

Growth hormone (GH) and IGF-1 have long been recognized as drivers of physical growth, but this comprehensive review published in Physiology (Bethesda) makes a compelling case that the somatotropic axis is equally critical for brain health across the lifespan. GH receptors (GHRs) are expressed throughout the brain — most densely in the hypothalamus but also in the hippocampus, amygdala, bed nucleus of the stria terminalis, cerebral cortex, cerebellum, thalamus, and multiple brainstem nuclei. The review details how GH crosses the blood-brain barrier and activates STAT5 signaling in neurons, and how a GHR-reporter mouse model confirmed these findings structurally, establishing the brain as a direct hormonal target.

IGF-1's role in brain development is particularly well-documented. Mouse models with IGF-1 overexpression develop brains with more neurons and oligodendrocytes, while IGF-1 or IGF-1 receptor knockout mice show significant brain growth retardation. Mechanistically, IGF-1 regulates glutamate receptor subunit expression in the hippocampus — proteins essential for memory formation — and mediates GH-treatment benefits on hippocampal plasticity and learning. IGF-1 also governs brain glucose uptake, myelination, and adult cerebrovascular remodeling, potentially explaining exercise-induced angiogenesis in the brain. Notably, GH- or GHR-deficient mice are paradoxically protected against age-related cognitive decline, attributed to improved insulin sensitivity and reduced neuroinflammation and inflammasome activation with aging.

For neurodegenerative diseases, the evidence is striking. Low serum IGF-1 is associated with elevated brain amyloid-beta levels, a hallmark of Alzheimer's pathology, and Alzheimer's patients show brain IGF-1 resistance. In Parkinson's models, dopaminergic midbrain neurons both express IGF-1 receptors and produce local IGF-1 after depolarization; IGF-1 knockout in these neurons reduces striatal dopamine, impairs neuronal firing, and diminishes locomotion and learning. IGF-1 gene therapy in a rat Parkinson's model prevented cognitive deficits, elevated tyrosine hydroxylase in the striatum, and improved the anti-inflammatory profiles of microglia and astrocytes. GH treatment for 21 days in a rat Parkinson's model improved motor function and dendrite morphology of dopaminergic neurons.

The review presents strong evidence for GH/IGF-1 involvement in mood and stress disorders. Mice lacking the Ghrh gene show reduced GH and IGF-1 with decreased anxiety and depression-like behaviors. GH treatment reversed anxiety and depression-like behavior in rats subjected to 21 days of total sleep deprivation. Critically, mice with GHR selectively deleted from somatostatin-expressing neurons showed increased anxiety across multiple validated tests (open field, elevated plus maze, light-dark box) — but only in males, not females — without any changes in GH secretion, IGF-1, body weight, or metabolism. This finding pinpoints a direct, circuit-specific anxiolytic role for GH. For PTSD, chronic stress activates a ghrelin-GH-IGF-1 axis in the amygdala, enhancing fear memory consolidation; pharmacological GHR antagonism blocks this fear-potentiating effect, identifying a potential therapeutic target.

In human studies, GH deficiency is associated with depression, anxiety, and fatigue — symptoms reversible with GH replacement. IGF-1 serum levels correlate with Alzheimer's disease risk, and GHRH administration modulates neuronal exosome biomarkers in mild cognitive impairment. The review also links GH/IGF-1 dysregulation to schizophrenia, bipolar disorder, autism spectrum disorder, and ADHD, though human evidence for these remains more preliminary. The authors call for future clinical trials investigating GH, IGF-1, and ghrelin-based interventions for neuropsychiatric conditions, and for mechanistic studies to clarify the interplay between the somatotropic axis, neuroinflammation, and insulin signaling in aging brains.