Recent research has identified osteocalcin (OCN), an endocrine hormone primarily associated with bone health, as a significant player in brain function, opening new avenues for addressing mood disorders and cognitive impairments. OCN, produced by osteoblasts, is known to regulate male fertility, energy expenditure, and glucose homeostasis. However, its ability to cross the blood–brain barrier and influence neurotransmitter synthesis has now come to the forefront of scientific inquiry.
In a groundbreaking study published on March 24, 2025, researchers from Friedrich-Alexander University Erlangen-Nuremberg employed multiparametric magnetic resonance imaging (MRI) to investigate the effects of intravenously administered OCN on the wild-type mouse brain. Their findings suggest that OCN significantly impacts regions involved in cognition, anxiety, and depression.
Understanding the role of OCN in the brain is not merely academic. Previous studies have indicated that a lack of OCN is associated with anxiety and depression-like behaviors in mice, raising questions about its potential therapeutic implications for humans experiencing similar mental health challenges. As neuropsychiatric diseases continue to rise globally, insights into the underlying biological mechanisms could inform innovative treatment approaches.
The researchers selected female C57BL/6J mice for their studies, utilizing a control group that received sodium chloride and an experimental group that received OCN. This rigorous experimental design involved two distinct MRI measurements: resting state functional MRI (rs-fMRI) and pharmacological MRI (phMRI), effectively capturing the dynamic interplay between OCN and the brain's neurovascular activity.
Analysis showed that OCN strongly influenced four critical brain regions: the brainstem, limbic output, association cortex, and basal ganglia, all of which are highly relevant in mediating OCN’s effects. Notably, within these regions, gene expression analysis revealed that the receptors for OCN, GPR37 and GPR158, are notably expressed, effectively bridging the role of this hormone with neurotransmitter activity—a connection pivotal for mood regulation.
The results identified significant increases in regional cerebral blood volume (rCBV) in the thalamus, hypothalamus, and other emotional processing centers post-OCN injection, underscoring the hormone's ability to modulate blood flow in response to neurochemical changes. The study documented the highest number of significantly altered connections occurring 34 minutes after OCN administration, suggesting a critical window during which OCN's effects are most pronounced.
As the amygdala emerged as a key hub, the researchers noted that some connections within this region were significantly stronger in the OCN group than in the control. This supports the notion that OCN not only influences direct regions of neurotransmitter processing but modulates broader network connectivity across diverse brain areas associated with mood and cognition.
Moreover, the study's authors posited that the linkage between OCN and neurotransmitter function, notably serotonin and norepinephrine, may corroborate the monoamine deficiency hypothesis often implicated in the pathology of depression. "This study provides the first imaging data of the physiological impact of OCN on the mouse brain, suggesting its potential role in modulating brain function and its relevance as a candidate for further investigation in anxiety, depression, and cognitive impairments," they wrote.
The trajectory of OCN's influence on the brain extends beyond immediate actions; its levels decline with age, correlating with diminished cognitive performance and heightened anxiety-like behaviors. The researchers noted that enhancing OCN levels through therapeutic means could potentially reverse age-related cognitive decline, as indicated by experiments showing performance improvements in aged mice receiving younger plasma containing OCN.
Furthermore, the implications of OCN stretch into broader discussions about the gut-brain axis, as dietary factors influencing bone health may also affect mood and cognition through OCN signaling pathways. Owing to the intricate relationship between bone health and mental well-being, further explorations into OCN’s neurophysiological roles could catalyze novel interventions targeting depression and anxiety.
In summary, this comprehensive study highlights the essential functions of osteocalcin in brain physiology, suggesting that it serves as a precursor for potential therapeutic applications in mental health and cognitive enhancement. As a fundamental link between physical health, bone status, and psychological well-being is increasingly recognized, osteocalcin's multifaceted benefits convey substantial promise for advancing treatment approaches to anxiety and depression.
