Abstract
Abstract
The Role of Ovarian Steroids in the Glucocorticoid Receptor
System
One of the most common clinical findings in patients with major
depressive disorder
(MDD) is hyperactivity of the hypothalamic-pituitary-adrenal (HPA)
axis, the system in the body
that regulates the stress response. It has been suggested that
alterations in the
glucocorticoid receptor (GR)-mediated feedback prolongs activation
of the HPA axis, leading to
the dysfunction observed in MDD. Additionally, the risk for
developing MDD is heightened by
several risk factors, namely gender, genetics and early life
stress. Previous studies from our lab
showed a sexually dimorphic change in the molecular regulation of
GR activity in females
following early life stress, which could mediate their heightened
risk to HPA axis dysfunction.
The purpose of this project was to determine whether steroid
hormones mediate the altered
adaptation of the GR chaperone system during stress in hippocampal
neurons. Methods: First, we
examined whether GR translocation was altered in the hippocampi of
female rats that had a
history of chronic adolescent stress. Next, we determined the
extent to which serum ovarian
steroid levels, stage of estrous, and uterine weights predicted
expression of Gr and two co-
regulators: Fkbp5 and Ppid. Finally, we assessed the
impact of corticosterone (cort), estradiol
(E2), and progesterone (P4) treatments on the expression of these
genes in vitro in HT-22
hippocampal neurons. Results: Compared to control female
animals, females with a history of
chronic adolescent stress displayed an attenuated increase in GR
translocation that was induced
by a forced swim test. The amount of GR, however, did not change
due to chronic stress,
suggesting a difference in the molecular regulation of GR. Uterine
weights predicted expression
of Fkbp5 and Ppid but did not predict expression of
Gr. Additionally, treatment of HT-22 cells
with increasing doses of cort increased the expression of
Fkbp5, an effect that was potentiated
decreased the expression of Ppid.
Collectively, these results suggest that the expression of GR
co-regulators is directly influenced
by exposure to gonadal steroids, and provides a basis for the
attenuated GR translocation that we
observed in females with a history of chronic stress.
Table of Contents
Table of Contents
INTRODUCTION...1
METHODS...14
RESULTS...24
DISCUSSION...27
TABLES AND FIGURES...40
Table 1...40
Table 2...41
Table 3...42
Figure 1...43
Figure 2...44
Figure 3...45
Figure 4...46
Figure 5...47
Figure 6...48
Figure 7...49
Figure 8...50
Figure 9...51
REFERENCES...52
About this Honors Thesis
Rights statement
- Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
| School |
|
|---|
| Department |
|
|---|
| Degree |
|
|---|
| Submission |
|
|---|
| Language |
|
|---|
| Research Field |
|
|---|
| Palavra-chave |
|
|---|
| Committee Chair / Thesis Advisor |
|
|---|
| Committee Members |
|
|---|