PTH-Induced Behavioral and Metabolic Alterations in Mouse Models of Hyperparathyroidism

Parathyroid hormone (PTH) is a critical endocrine regulator of calcium homeostasis and bone remodeling and is widely employed in clinical settings through synthetic analogs for the treatment of osteoporosis. Although traditionally considered a peripheral regulator, emerging evidence indicates that PTH also exerts effects through the central nervous system (CNS). This study investigated the neuropsychiatric impact of elevated PTH and explored potential CNS involvement using multiple murine models of hyperparathyroidism (HPT). Distinct behavioral phenotypes were observed across models, indicating that psychiatric symptoms vary depending on disease etiology and progression. The effects of hPTH(1-34), a clinically approved PTH analog, were further assessed in male and female mice. Under pharmacological concentrations, hPTH(1-34) enhanced locomotor activity in males but induced mild anxiety-like behavior in females. These behavioral changes in females were independent of the estrus cycle and were amplified by ovariectomy. Metabolic analysis indicates PTH affects the basic metabolism by inhibiting the respiratory exchange ratio, promotes the energy expenditure and locomotion without affecting the food consumption in a 48hr range. To further investigate the molecular effect of PTH in the brain, a PTH1R-Cre mouse line was generated to map PTH receptor-1 (PTH1R) expression. Widespread expression of PTH1R was detected across the brain, including in both neuronal and non-neuronal cell populations. These findings suggest that PTH may influence behavior through interactions with PTH1R-expressing cells in brain vasculature and circumventricular regions. However, further studies are warranted to define the specific brain nuclei and cell types involved in PTH-driven modulation of neurobehavioral function.