Li, Junyi
(2018)
LOCAL ESTROGEN PRODUCTION IN THE BRAIN AND ITS REGULATION UNDER PATHOLOGICAL CONDITIONS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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 cholinesterase inhibitor (ChEIs) injections, did not regulate ARO and ERs in the cortex and hippocampus; 4) In
the cortex, there was a significant increase of long-form ARO in females and a significant increase of ER alpha in both sexes, indicating an induction of estrogen signaling in the cortex after CCI. In the hippocampus, the long-form ARO expression was significantly decreased in both sexes with an increase of ER beta in males after CCI. Overall, this dissertation provides novel methods and important information about brain estrogen production within the field of neuroendocrinology.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
3 December 2018 |
| Date Type: |
Publication |
| Defense Date: |
27 June 2018 |
| Approval Date: |
3 December 2018 |
| Submission Date: |
26 November 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
139 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
CYP,Sex hormone,Distribution |
| Date Deposited: |
03 Dec 2018 15:06 |
| Last Modified: |
03 Dec 2018 15:06 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35602 |
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