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Research Topics
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 Research Topics    |    Major Focus Areas
Research Topics
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Genetic Studies
Project Summary

Title: Neurological and Circadian Substrates of PTSD-like Behaviors
Synopsis: This study attempts to determine if the development of post-traumatic stress disorder (PTSD) requires both a traumatic event and a genetic (neurological) susceptibility (since not all individuals who experience a traumatic event develop PTSD).
Overall Project Objective: Examine both manifestations of genetic vulnerabilities and behavioral sensitization processes that might contribute to the development of posttraumatic stress disorder (PTSD). The rationale is that the development of PTSD requires both a traumatic event (behavioral or environmental sensitization) and a genetic component (as not all individuals who experience a traumatic event develop PTSD). The genetic models will be strains of rats that exhibit abnormal behavioral and physiological responses to stress.
Status/Results to Date: Demonstrated several differences between the three strains that are relevant to understanding the interactions between genetic predisposition and stress susceptibility. Verified that the Lewis rats showed blunted secretion of acetylcorticotropic hormone (ACTH) to acute stress, and the WKY response was exaggerated. Completed an analysis of brain noradrenergic reactivity to acute-immobilization stress in three rat strains. Noradrenergic reactivity was assessed by measuring tyrosine hydroxylase (TH) mRNA expression in locus coeruleus, and norepinephrine (NE) release in the lateral bed nucleus of the stria terminalis (BSTL). Behavioral measures of arousal and stress reactivity included locomotion in a novel environment, fear-potentiated startle, and stress-induced reductions in social behavior and open-arm exploration in the elevated-plus maze. Compared to SD, LEWIS rats showed blunted ACTH responses, but similar behavioral responses to stress. They showed similar elevations of TH mRNA, and slightly greater NE release in BSTL during stress, although both noradrenergic responses returned toward baseline more rapidly than in SD rats. By contrast, WKY rats had a greater ACTH response than SD, but depressed startle, reduced baseline exploratory and social behavior, and a lack of both fear-potentiated startle and stress-induced reductions in exploratory and social behavior, indicating reduced arousal and attenuated behavioral stress reactivity. Noradrenergic reactivity to stress was attenuated in WKY, showing less TH mRNA elevation and reduced NE release. These results suggest that WKY rats have deficient brain noradrenergic reactivity, associated with reduced arousal and behavioral reactivity, which may inhibit their ability to cope with stress, resulting in exaggerated neuroendocrine responses and susceptibility to stress-related psychopathology. Found that control Sprague-Dawley animals undergoing sensitization either by kindling or by cold stress exhibit an enhanced level of anxiety on the behavioral tests.
Project:DoD-91
Agency:Department Of Defense
Location:Armstrong Lab
VAMC San Antonio
P.I. Name:Alan Frazer, Ph. D
Research Type:Mechanistic
Research Focus:Brain & Nervous System
Focus Category:Genetic Studies
Status:Ongoing
Study Start Date:October 01,1998
Estimated Completion Date:September 30,2001
Specific Aims: (see Methodology)
Methodology: The strains of rat we are comparing are the inbred Wistar Kyoto rat (WKY), the inbred Lewis rat, and the control out-bred comparator Sprague-Dawley rat (SD). The WKY rat is more vulnerable to the pathological effects of stress, and demonstrates an exaggerated hormonal stress response but an attenuated behavioral response (behavioral inhibition rather than activation). By contrast, the Lewis rat has a blunted hormonal response but a normal behavioral response as compared to the control SD rats. Thus, by using these strains, the investigators are able to dissociate regulation or dysregulation of neural processes involved in neuroendocrine vs behavioral responses to stress.
Most Recent Publications:

Foster D, Strong R, Morgan WW. A tetracycline-repressible transactivator approach suggests a shorter half-life for tyrosine hydroxylase mRNA. Brain Res, 7(2):137-46, Jun 2001. Abstract

Sands SA, Corbitt J, Strong R, Morilak DA. Acute stress-induced changes in gene expression in locus coeruleus of rat strains defined by stress susceptibility and reactivity. Soc Neurosci Abs, 25:76, 1999. Abstract

Sands SA, Strong JR, Corbitt J, Morilak DA. Behavioral inhibition in Wistar Kyoto rats associated with a lack of brain noradrenergic reactivity to stress and reduced benzodiazepine binding in limbic forebrain. Society for Neuroscience, 2000. Abstract

Sands SA, Strong R, Corbitt J, Morilak DA. Effects of acute restraint stress on tyrosine hydroxylase mRNA expression in locus coeruleus of Wistar and Wistar-Kyoto (WKY) rats. Mol Brain Res, 10;75(1):1-7, Jan 2000. Abstract

Hagerty T, Morgan WW, Elango N, Strong R. Identification of a glucocorticoid-responsive element in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochem, ;76(3):825-34, Feb 2001. Abstract

Hagerty T, Fernandez E, Lynch K, Wang S, Morgan WW, Strong R. Interaction of a glucocorticoid-responsive element with regulatory sequences in the promoter region of the mouse tyrosine hydroxylase gene. Journal of Neurochem, 78(6):1379-88, Sep 2001. Abstract

Cecchi M, Khoshbouei H, Javors M, Morilak DA. Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience, 112(1):13-21, 2002. Abstract

Corbitt J, Hagerty T, Fernandez E, Morgan WW, Strong R. Transcriptional and post-transcriptional regulation of Tyrosine Hydroxylase messenger RNA in PC12 cells during persistent stimulation by VIP and PACAP38: differential regulation by protein kinase A and protein kinase C -dependent pathways. Neuropeptides, 36(1):34-45, Feb 2002. Abstract