Thyroid hormone excess targeted to oxytocin neurons disrupts oxytocin physiology without impacting behavior.

Abstract

Deficiencies in oxytocin are associated with neurodevelopmental and behavioral disorders, and the oxytocin gene (Oxt) can be regulated by thyroid hormone. We have previously shown that a systemic excess of thyroid hormone during development causes deficits in oxytocin that are associated with major abnormalities in mood-related and social behaviors. To determine whether the disruption in oxytocin physiology is responsible for these aberrant behaviors we targeted thyroid hormone excess to oxytocin neurons using a mouse model of conditional deficiency of the type 3 deiodinase (DIO3), the neuronal enzyme responsible for the clearance of thyroid hormones and the modulation of thyroid hormone action. We observed that mice of both sexes with T3 excess in oxytocin neurons largely recapitulated the oxytocin deficits of systemic thyrotoxicosis, and exhibited reduced neonatal and adult hypothalamic expression of Oxt mRNA, markedly blunted pituitary Oxt expression and lower serum levels of oxytocin. However, these mice did not show any significant abnormality in physical activity levels, depression- and anxiety-like behaviors, aggression, sociability or maternal behavior. We conclude that T3 excess in mouse oxytocin neurons is sufficient to cause significant oxytocin deficits, but insufficient per se to cause detectable abnormalities in behavioral profiles. Our results suggest that the profound behavioral syndrome previously observed in mice with systemic developmental thyrotoxicosis likely involves other brain neural circuits affected by developmental T3 excess that remain to be identified.