The Effects of Progesterone Receptor on Development of Serotonergic Circuits that Mediate Cognition

As the rate of premature births has been substantially increasing, progestin administration is becoming a common treatment for the prevention of preterm labor. However, not much is known regarding how these hormonal supplements may affect the development of the fetal brain. The developing brain is highly sensitive to progesterone as progesterone receptor (PR) is expressed in many regions during critical developmental periods. Steroid hormone receptors such as PR are powerful transcription factors and regulate gene expression to alter fundamental processes of neural development. During the developmental period of post-natal day one (P1) to P14 in rats, PR is transiently expressed in the medial prefrontal cortex (mPFC), suggesting an important developmental influence. The mPFC is an area critical area of the brain for higher-order cognition, so modulation of the effects of PR is assumed to have behavioral implications. In this study, male rat pups were treated daily from the day of birth (P1) to P14 with the progesterone receptor antagonist RU486 (20 mg/kg) or an equal volume of the sesame oil vehicle as a control (during the precise critical developmental period when PR is transiently expressed), and cognitive flexibility was tested using the attentional set-shift task plus maze. In the maze itself the arms are painted either light or dark and their texture is either smooth or rough. Animals are trained to receive a food reward using one cue (e.g., reward in light arms). After the task is learned the “rule” is changed (e.g. food reward only in rough arms) and the rats must “shift” to the new rule to receive a reward. They must inhibit the previously learned response and demonstrate cognitive flexibility. RU486 treated rats demonstrated a significant impairment in cognitive flexibility and an increase in perseveration. Specifically, they were slower to shift to the new rule and were EFFECTS OF PR ON SEROTONIN AND COGNITION 3 more likely to continue to use the old rule compared to control rats. This difference suggests a disruption in higher-order cognition. Serotonin activity in the mPFC has been shown to affect cognitive flexibility, the ability to alter behavioral strategies after changes in reward contingencies. Therefore, we treated an additional cohort of rats with RU486 or oil during development, as described above and collected adult tissue to analyze serotonergic fiber density in the mPFC. Because PR is expressed in serotonergic midbrain nuclei and serotonergic target regions of the medial prefrontal cortex, this study tested the hypothesis that PR activity plays a role in development of mesocortical serotonergic pathways and in the display of complex cognitive behavior in adulthood. At P36, brain tissue was collected and sectioned on a sliding microtome at 50μm. Immunocytochemistry was used to detect serotonin fibers in the mPFC, which receives extensive serotonergic projections, and as mentioned previously, expresses PR during development. Analysis is still in progress, however it is predicted that RU486 treatment will significantly alter serotonin fiber density in this area, which is critical for complex cognitive behaviors. In conclusion, we hypothesize that PR activity during development is critical for cognitive functioning and that this may be due to its effects on the serotonergic system. This suggests the need for further research to determine the potential negative effects of hormone-based treatments for the prevention of premature births. EFFECTS OF PR ON SEROTONIN AND COGNITION 4 The Effects of Progesterone Receptor on Development of Serotonergic Circuits that Mediate Cognition