LOCAL ESTROGEN PRODUCTION IN THE BRAIN AND ITS REGULATION UNDER PATHOLOGICAL CONDITIONS

Estrogens have important roles in regulating brain structure and function. Estrogens are produced by conversion of androgens via the enzyme aromatase (ARO). ARO is expressed in specific regions of the brain, and recent studies suggest that local estrogen may have a greater impact on neuronal survival and plasticity than systemic one. In this dissertation study, I developed UPLC-MS/MS based assays to measure ARO activity and estradiol (E2) in the rat brain tissues. I also detected the E2 levels in the brain and compared with that in the serum in rats given different E2 and testosterone treatments. Moreover, I tested the effect of manipulating cholinergic systems and the effect of traumatic brain injury (TBI) on the expression of different isoforms of ARO and estrogen receptors (ER) in different brain regions. Results demonstrate that 1) the microsomal-based assay to detect ARO activity is highly sensitive, specific and reliable. By applying this method, I demonstrated a correlation between ARO activity and its long-form mRNA, and that their distribution was in accord with previous studies; 2) that E2 levels in brain regions with ARO are higher than that in serum in ovariectomized rats treated with different doses of estradiol benzoate and testosterone propionate. Letrozole (an ARO inhibitor) treatment reversed the differences between brain and serum estradiol levels, demonstrating that the differences were due to local estradiol production. Moreover, male rats had substantial levels of E2 in specific regions of the brain even though levels in the systemic circulation were not detectable; 3) Selective cholinergic lesions in the medial septum and daily …