The Role of Progesterone Receptor in the Development of the Mesocortical Dopaminergic Pathway.

摘要

In this thesis, I describe the expression of nuclear progesterone receptor (PR) in both the origin and targets of the mesocortical circuit, the phenotype of the cells that express PR within this system, the effects of PR inhibition on the development of mesocortical circuits and the display of PFC-mediated behaviors. In addition, I examine the effects of exogenous administration of a commonly prescribed synthetic progestin on mesocortical functioning.;In chapter 2, the full ontogeny of PR expression in both the developing ventral tegmental area (VTA) and medial prefrontal cortex (mPFC) in males and females is provided. PR is transiently expressed without a sex difference in both the VTA and medial PFC during partially overlapping and partially distinct neonatal periods. It is also shown that PR within the neonatal VTA is expressed primarily in dopaminergic cells, as over 90% of PR immunoreactive cells were also immunopositive for tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. Retrograde tract-tracing with Fluorogold confirmed that many of these PR-containing cells of the VTA do in fact project directly to the mPFC, suggesting that PR is expressed in dopaminergic projection neurons of the mesocortical pathway. In chapter 3, I explore the role of PR inhibition on TH expression and cell number in the VTA, along with TH fiber density in the mPFC in the pre-adolescent period and adulthood. Results demonstrate that neonatal inhibition of PR with the PR antagonist RU486 decreases the density of TH immunoreactive (ir) fibers in the Prelimbic (PL) mPFC at postnatal day (P) 25 and decreases TH expression, but not THir cell number, in the VTA in adulthood. Additionally, in progesterone receptor knockout (PRKO) mice lacking functional PR, TH expression in the adult VTA was also reduced compared to controls. These results suggest that PR activity may exert long-lasting effects on TH levels in the VTA, and perhaps more transient effects on connectivity patterns in the mesocortical circuit. In chapter 4, I examine the effects of PR inhibition on the display of cognitive behaviors in adulthood. The tasks utilized for these experiments, novel object recognition, inhibitory avoidance and the attentional set-shift task, are all, to some degree, mediated by mPFC activity. Inhibition of PR activity with RU486 during development impaired adult performance on each of these three tasks, yet did not alter behavior on an open field task, suggesting that RU486 treatment resulted in cognitive impairment and not differences in anxiety or motor ability. In addition, adult PRKO displayed an impaired performance on an adapted water maze task measuring cognitive flexibility, a deficit that coincided with an increase in perseveration. Lastly, in chapter 5, I examine the effects of neonatal administration of the synthetic progestin 17&agr;-hydroxyprogesterone caproate (17P) on development of the mesocortical system, along with cognitive flexibility ability in adulthood. It was found that, in a dose-dependent manner, 17P treatment increased TH expression in the VTA, and significantly increased TH fiber density in the PL mPFC. 17P treatment also impaired performance on the attentional set-shift task, and increased perseveration errors, suggesting that neonatal treatment with 17P exerts organizational effects on the mesocortical system that manifest in cognitive deficits in adulthood.;Collectively, the present findings suggest that PR activity during development may play an important role in the establishment of functional connections of the mesocortical dopaminergic pathway through actions in the VTA and/or in target cells of the mPFC. These results have implications for the future treatment of clinical disorders associated with dysfunction of the mesocortical circuit such as ADHD and schizophrenia. Additionally, these findings suggest that the developing brain is highly sensitive to the actions of progesterone and/or synthetic progestins, suggesting caution in the use of progestins in women to treat premature birth. Lastly, results of this thesis also provide evidence for a novel mechanism by which steroid hormones and their receptors affect neural development and behavior. (Abstract shortened by UMI.).