Date of Award

Spring 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

First Advisor

Paul J. Gasser

Second Advisor

David Baker

Third Advisor

John Mantsch

Abstract

Post-traumatic stress disorder (PTSD), an anxiety disorder precipitated by exposure to extreme emotional and/or physical stress, is characterized by persistent, intrusive memories of the precipitating trauma. Thus, the pathogenesis of PTSD has been conceptualized as involving a deficit in consolidation mechanisms underlying the extinction of fear memory. The mechanisms underlying this deficit have not been elucidated. In addition to intrusive memories, patients with PTSD display heightened sensitivity of the hypothalamic pituitary adrenocortical (HPA) axis to glucocorticoid negative feedback. As glucocorticoids are important modulators of memory consolidation, increased sensitivity to HPA negative feedback, by blunting glucocorticoid responses, may contribute to memory-related symptoms in PTSD patients. Emerging evidence in human patients suggests that the observed heightened negative feedback sensitivity in PTSD patients represents a marker of susceptibility to developing PTSD, rather than an effect of exposure to trauma, but this hypothesis has not been tested in animal studies. We examined individual differences in HPA responsiveness in rats displaying low (LR) and high (HR) locomotor responses to novelty. LR rats exhibited increased anxiety-like behaviors and less motility as compared to HR rats. HR rats displayed larger increases in corticosterone in response to restraint stress as compared to LR rats. LR and HR rats were subjected to contextual fear conditioning in order to examine consolidation, incubation, and extinction effects. LR rats exhibited increased freezing time and a reduction in the ability to extinguish fear memory as compared to HR rats. Additional animals were measured for acoustic startle prior to and following exposure the animal PTSD-model single-prolonged stress. LR rats subjected to a SPS exhibited a small increase in freezing indicative. HR rats expressed slightly lower levels of startle amplitude for most conditions, suggestive of habituation between trials. Overall, LR rats provide a working model to examine how individual differences in the HPA axis stress response play a role in the formation of PTSD-like behaviors.

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