The path to the parous brain: allopregnanolone-mediated mechanisms at GABAA receptors. - Project Summary By age 49, nearly 85% of women in the US will have given birth at least once. The pregnancy and postpartum periods are marked by extreme hormonal fluctuations that can induce long-lasting changes in the brain, but mechanistic insight into how the unique hormonal milieu that characterizes pregnancy produces stable alterations in neural activity and behavior is lacking. The medial prefrontal cortex (mPFC)—a brain region critical to higher-order processes like executive function, emotion regulation, and decision-making—has been especially under-studied in parous animals, despite reports of alterations in these functions in parous women. Our lab has collected intriguing preliminary data in rats suggesting that during late pregnancy, neural activity in the mPFC is markedly suppressed compared to that of nulliparous (NP) animals. After weaning, however, we found that mPFC activity swings well past that of NP, suggesting that the brain undergoes an over-compensatory rebound from the pregnancy after parturition. The main goal of this proposal is to investigate the specific role that the hormone allopregnanolone (AP)—whose levels are notably high during late pregnancy—plays in producing this effect. AP acts as a positive allosteric modulator at the GABAA receptor, making it a potential driver of the neural inhibition we observe in late pregnancy. Here we will test the hypothesis that allopregnanolone-mediated GABA signaling is both necessary and sufficient for producing the long-term alterations in mPFC function observed in primiparous animals. The Aims that comprise this proposal integrate pharmacological, chemogenetic, and CRISPR/Cas9-based manipulations to either block or mimic AP-related processes during late pregnancy. We will then use fiber photometry to measure mPFC activity during recall of conditioned fear (which relies on optimal mPFC function) at post-weaning timepoints. Together, these experiments are able to establish a causal, mechanistic link between the pregnant and primiparous brain.
