PTH-induced behavioral and metabolic alterations in mouse models of hyperparathyroidism

Parathyroid hormone (PTH), a well-established regulator of calcium homeostasis and bone remodeling, has been implicated in central nervous system (CNS) modulation beyond its classical peripheral endocrine functions. Utilizing multiple murine models of hyperparathyroidism, this study demonstrated that elevated PTH produces distinct behavioral phenotypes contingent upon disease etiology and progression. Administration of hPTH(1-34) elicited sexually dimorphic behavioral responses - enhanced locomotor activity in males and anxiety-like behavior in females - the latter being independent of estrus cycle phase yet potentiated by ovariectomy. Metabolic analyses further revealed that PTH modulates energy expenditure and respiratory exchange ratio without altering food consumption. Employing a newly generated PTH1R-Cre mouse line, widespread PTH receptor-1 (PTH1R) expression was identified across diverse neuronal and non-neuronal cell populations, including brain vasculature and circumventricular organs. Collectively, these findings support a CNS-mediated mechanism underlying PTH's neurobehavioral effects, warranting further investigation into the specific neural substrates involved.