Sex differences in dopamine innervation and microglia are altered by synthetic progestin in neonatal medial prefrontal cortex

Abstract

The synthetic progestin 17‐α‐hydroxyprogesterone caproate (17‐OHPC) is commonly prescribed to pregnant women with a history of preterm delivery, despite little evidence of efficacy. The timing of 17‐OHPC administration coincides with fetal mesocortical dopamine pathway development, yet the potential effects on cortical development and cognition are almost unknown. In rodent models, exposure to 17‐OHPC significantly increased dopaminergic innervation of the medial prefrontal cortex (mPFC), an aberrant pattern of connectivity that may underlie deficits in cognitive flexibility observed in adulthood. In the present study, tyrosine hydroxylase (TH) immunoreactivity was used to determine whether 17‐OHPC altered dopaminergic innervation of the mPFC during a neonatal period of synaptogenesis in males and females. Although there were no differences in the amount of TH‐immunoreactive (‐IR) fibres, there was a sex difference in TH‐IR fibre distribution in deep layers of the prelimbic area (PL) mPFC; males had a narrower pattern of dopaminergic innervation than females. 17‐OHPC exposure abolished these sex‐specific patterns, such that 17‐OHPC females had a narrower pattern in the PL than control females. In the infralimbic mPFC (IL), 17‐OHPC males had a broader pattern of distribution of TH‐immunoreactivity than control males with no differences in the amount of TH‐IR fibres. 17‐OHPC also created a sex difference in which males had a lower TH‐IR fibre density than females. We also examined microglia, brain macrophages that play a key role in sculpting dopaminergic axon outgrowth in development, using phenotype as an indirect measure of microglial activity. Females had a greater number of reactive stout microglia compared to males in the PL, and males had more active round microglia than females in the IL. 17‐OHPC treatment abolished the sex differences in both regions. These findings demonstrate that developmental exposure to 17‐OHPC can exert differential effects in males and females and may diminish sex differences in cortical maturation.