Chronic stress has been shown to be associated clinically with formation of depression in patients and hormones are known to mediate certain clinical manifestations of mood disorders. Although the precise mechanisms underlying these effects remain to be elucidated, increasing data suggests that an alteration in neuroprotection and mitochondrial functions may play an important role. The primary objective of this study is to understand the mitochondrial functions regulated by hormones during chronic stress. Cortical neuronal cultures were established in order to determine the localization of GR in the mitochondria and its function in mitochondria. GR levels in mitochondria were decreased after corticosterone (10-7M) treatment in cultured cortical neurons. In addition, mitochondrial oxidation function was enhanced after one day treatment of corticosterone (10-7M), determined by MitoTracker Red staining. Consistent with the enhancement of mitochondrial function, mitochondrially encoded gene cytochrome oxidase I (COXI) (has GRE in its promoter region) expression was also increased in mitochondria. In order to determine the role of Bag-1 in regulating GR function, we found that total Bag-1 protein expression was decreased in cell homogenates, however, Bag1 distribution in mitochondria was increased, suggesting an important role in regulating GR effects. Collaborating with Bruce McEwen?s lab, we will use a well-established chronic-stress paradigm to study the function of glucocorticoid receptor in mitochondria in vivo by biochemical and immunocytochemical method. These studies may provide additional insights on the mechanisms by which hormones regulate mitochondrial function and neuronal signaling. Furthermore, this research also have the potential to contribute to a more complete understanding of the mechanisms by which chronic stress and hormones regulate neuroplasticity and neuronal survival, and to the future development of improved therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH002840-01
Application #
6982757
Study Section
(LMP)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code