The Role of Ovarian Steroids in the Glucocorticoid Receptor System Open Access

Malviya, Sanjana (2012)

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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.

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