Date of Award

2017

Document Type

Open Access Thesis

Department

Biomedical Science

Sub-Department

School of Medicine

First Advisor

David Mott

Second Advisor

Marlene Wilson

Abstract

Post-Traumatic Stress Disorder (PTSD) is a mental health disorder that can occur following a traumatic event like combat, assault, or disaster. Individuals with PTSD are unable to extinguish fear memories which can become chronic and disabling. However, it remains unclear why some individuals exposed to a traumatic event develop PTSD while others are resilient. Acetylcholine plays a critical role in fear learning, but its role in fear extinction is less well understood. In this investigation, we used a rat model of fear extinction to determine if individual differences in extinction learning are correlated with markers of cholinergic signaling. Cholinergic markers included the M1 muscarinic acetylcholine receptor (M1 m-AChR) and the vesicular acetylcholine transporter (vAChT). These cholinergic markers are strongly expressed in brain regions, such as the amygdala and prefrontal cortex that contribute to the fear extinction circuit. The goal of the present study was to determine whether individual differences in cholinergic signaling in these brain regions could underlie differences in fear extinction. Expression levels of cholinergic markers were measured in amygdala and prefrontal cortex from male Long-Evans rats (N = 13) that had undergone a Pavlovian fear conditioning and extinction paradigm. We found that rats exhibited individual differences in extinction of freezing behavior following twenty presentations of a conditioned auditory stimulus. Six of 13 rats tested failed to extinguish cue-conditioned freezing behavior as defined by a median split in freezing during the last 10 tone presentations. When M1 m-AChR expression in these animals was assessed by Western blot analysis, a significant correlation was evident between expression level of M1 m-AChR in the amygdala and the freezing behavior during the extinction trials. Expression of M1 m-AChRs in amygdala of animals showing good extinction learning was significantly higher than that in animals resistant to extinction. In contrast, there was no significant correlation between vAChT expression and freezing in either amygdala or prefrontal cortex. These results suggest that low expression of M1 m-AChRs in the amygdala is correlated with deficits in fear extinction, and suggest that therapeutic strategies aimed at enhancing muscarinic signaling in amygdala may enhance fear extinction in animals and perhaps patients with PTSD.

Rights

© 2017, Joshua R. McElroy

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