Abstract
BACKGROUND: Numerous psychiatric and behavioral disorders such as autism, attention deficit disorder and schizophrenia may involve disruptions in the development of the mesocortical dopamine pathway, consisting of dopaminergic projections from the midbrain ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC). Nuclear steroid hormone receptors are powerful transcription factors and can profoundly and permanently alter fundamental processes of neural development. Nuclear progesterone receptor (PR) is transiently expressed in both the VTA and the PFC of rodents during perinatal life, suggesting that PR may regulate the normal development of this important behavioral circuit. METHODS AND RESULTS: Here, we demonstrate that virtually all PR-immunoreactive (PR-ir) cells in the VTA also express tyrosine hydroxylase immunoreactivity (TH-ir). In addition, retrograde tract tracing reveals that many PR-ir cells in the VTA project to the mPFC. Administration of a PR antagonist to rats during the neonatal period decreased TH-ir fiber density in the prelimbic mPFC of juveniles (postnatal day 25) and decreased levels of TH-ir in the VTA of adults. Neonatal treatment with a PR antagonist impaired adult performance on a passive inhibitory avoidance task and an attentional set-shifting task, measures of behavioral inhibition/impulsivity and cognitive flexibility, respectively. TH-ir levels in the VTA were reduced and cognitive flexibility was impaired in PR knockout mice as well. CONCLUSIONS: These findings provide novel insights into a potential role for PR in the developmental etiology of behavioral disorders that involve impairments in complex cognitive behaviors and have implications for the use of synthetic progestins in humans during critical neurodevelopmental periods.