The Role of Progesterone Receptor in Development of Medial Prefrontal Cortex and Impulsive Behavior
Human behaviors are regulated by the complex functions of the brain and many behavioral disorders are assumed to be the result of alterations or deficits in neural function. Attention Deficit Hyperactivity Disorder (ADHD), characterized by differences in complex behaviors such as attention, memory and impulse control has been linked to alterations in dopaminergic activity in the medial prefrontal cortex (mPFC). Therefore, factors that regulate development of this region may be implicated in ADHD. For example, steroid hormones can alter fundamental processes of neural development through interaction with their nuclear receptors, which act as transcription factors. Progesterone receptor (PR) is transiently expressed in cerebral cortex during fetal and neonatal life in the laboratory rat, suggesting that progesterone and its receptor may play an important role in cortical development. The current study tested the hypothesis that PR activity during development plays an important role in the dopaminergic innervation of mPFC and in complex cognitive behaviors in adulthood. To test this hypothesis, animals were treated with a PR antagonist, RU486, or a control vehicle during postnatal development. On postnatal day 21 (P21) dopaminergic innervation of the mPFC was examined using immunocytochemistry for tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. Animals treated with RU486 had a significantly lower density of TH immunoreactive fibers in the prelimbic region of the mPFC, suggesting incomplete development of a key dopaminergic pathway. In addition, RU486 treated animals showed deficits on an inhibitory avoidance task, indicating that impulse control, memory and decision making may be impaired in these animals, behaviors that are regulated by dopaminergic afferents to the mPFC from the midbrain ventral tegmental area. These findings suggest that progesterone and its receptor play a previously overlooked role in the normal development cortical connectivity and subsequent cognitive behaviors. These findings may have implications for our understanding of developmental behavioral disorders involving the mPFC such as ADHD.