Uncontrolled psychological stress and associated abnormal cortisol hormone secretion patterns are a contributing factor to a number of pathophysiological conditions prevalent in our society, such as hypertension, atherosclerosis, insulin resistance, abdominal fat accumulation, asthma and altered immunity. There is an especially dynamic interplay between psychological stress and some psychological disorders, most notably depression and post traumatic disorder (PTSD). In both cases there is strong supporting evidence for dysregulation of Hypothalamic-Pituitary-Adrenal (HPA) axis activity, and the resulting dysregulated cortisol levels may contribute to some of the ongoing pathology. The most important factor controlling HPA axis activity is the negative feedback provided by glucocorticoids (e.g. cortisol and corticosterone). A comprehensive understanding of glucocorticoid negative feedback mechanisms is essential to determining the clinical basis of HPA axis dysregulation and its ramifications. We propose studies that will advance our understanding of the molecular, cellular and systems level aspects of glucocorticoid negative feedback. By monitoring stress-induced gene expression at multiple levels of the system (pituitary, hypothalamus and throughout brain) in parallel with stress-induced hormone secretion we can distinguish between the intrinsic (pituitary and hypothalamus) and extrinsic (throughout brain) glucocorticoid negative feedback actions. Our preliminary studies suggest that a stress-induced increase in glucocorticoids initiates negative feedback processes that temporally can be divided into three distinct phases: fast feedback (< 10 min), short-term feedback (about 1 hr) and delayed feedback (about 3 hr). Each phase is associated with different stress-induced gene expression patterns. By comprehensively examining the contribution of intrinsic and extrinsic sites of action and temporal patterns we will be able to accomplish the following Specific Aims: 1] Determine mechanisms by which phasic increases in glucocorticoids produce intrinsic negative feedback on the HPA axis functional response to psychological stress, 2] Characterize the extrinsic negative feedback influence on the HPA axis functional response to stress, 3] Characterize the impact of stress-induced increases of glucocorticoids on immediate and subsequent HPA axis responses to acute psychological stress. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH075968-02
Application #
7263898
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2006-07-20
Project End
2011-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$279,589
Indirect Cost
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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