Chronic stress and the adrenal steroids secreted in response to stress (e.g. cortisol, corticosterone) are associated with hippocampal atrophy in several conditions including Cushing's Syndrome, recurrent depressive disorder, and aging. Even veterans with posttraumatic stress disorder, a condition with reduced cortisol at the time of diagnosis, display reduced hippocampi, leaving open the possibility that cortisol was elevated during the period of hippocampal shrinkage. A recent study suggests that cortisol elevations contribute to hippocampal shrinkage because reducing chronically elevated cortisol in Cushing's patients reverses hippocampal atrophy. Given the breadth and significance of these cortisol-related afflictions, the long-term objective of this proposal is to understand the consequences and mechanisms by which chronic stress and cortisol hypersecretion cause hippocampal atrophy. Dendritic retraction of CA3 neurons in rats provides a useful model to study the effects of chronic stress and elevated corticosterone on the hippocampus. Chronic stress-induced changes in CA3 dendrites parallel the human condition by shrinking after chronic stress/corticosterone treatment and reversing when the stress subsides. Thus, the mechanisms underlying stress-induced dendritic retraction are conserved across species. The objectives of this proposal are to determine the effects of chronic stress or elevated corticosterone on mechanisms of CA3 dendritic retraction and their functional significance. To achieve this goal, this proposal has three specific aims. First, to determine whether chronic stress-induced CA3 dendritic retraction is indicative of neuronal degeneration or a protective response. Second, to ascertain the levels of corticosterone that are sufficient to cause CA3 dendritic retraction and memory impairment. Third, to determine whether psychosocial stress produces CA3 dendritic retraction and to reveal the components of hippocampal-dependent memory (such as acquisition, consolidation, retrieval) that are disrupted. In all studies, corticosterone, corticosterone binding globulin, and dehydroepiandrosterone will be measured to determine whether other components of the hypothalamic-pituitary-adrenal axis are disrupted by chronic stress and whether they correlate with CA3 dendritic retraction and memory deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064727-02
Application #
6658198
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Winsky, Lois M
Project Start
2002-09-12
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$202,965
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Ortiz, J B; McLaughlin, K J; Hamilton, G F et al. (2013) Cholesterol and perhaps estradiol protect against corticosterone-induced hippocampal CA3 dendritic retraction in gonadectomized female and male rats. Neuroscience 246:409-21
Hutchinson, Katie M; McLaughlin, Katie J; Wright, Ryan L et al. (2012) Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity. Neurobiol Learn Mem 97:250-60
Conrad, Cheryl D; McLaughlin, Katie J; Huynh, Thu N et al. (2012) Chronic stress and a cyclic regimen of estradiol administration separately facilitate spatial memory: relationship with hippocampal CA1 spine density and dendritic complexity. Behav Neurosci 126:142-56
McLaughlin, Katie J; Wilson, Jessica O; Harman, James et al. (2010) Chronic 17beta-estradiol or cholesterol prevents stress-induced hippocampal CA3 dendritic retraction in ovariectomized female rats: possible correspondence between CA1 spine properties and spatial acquisition. Hippocampus 20:768-86
Baran, Sarah E; Armstrong, Charles E; Niren, Danielle C et al. (2009) Chronic stress and sex differences on the recall of fear conditioning and extinction. Neurobiol Learn Mem 91:323-32
McLaughlin, Katie J; Bimonte-Nelson, Heather; Neisewander, Janet L et al. (2008) Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: evidence that the duration of hormone deprivation after ovariectomy compromises 17beta-estradiol effectiveness in altering CA1 spines. Horm Behav 54:386-95
Zoladz, Phillip R; Conrad, Cheryl D; Fleshner, Monika et al. (2008) Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress 11:259-81
Wright, Ryan L; Conrad, Cheryl D (2008) Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav Brain Res 187:41-7
Conrad, Cheryl D (2008) Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev Neurosci 19:395-411
Park, Collin R; Zoladz, Phillip R; Conrad, Cheryl D et al. (2008) Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats. Learn Mem 15:271-80

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