Mechanisms and Heterogeneity of Stress-Enhanced Fear Learning
Fear is critical for survival but can become harmful when it is disproportionate to the level of threat present. Post-traumatic stress disorder (PTSD) is characterized by such dysregulation of fear and is frequently comorbid with substance use disorders (SUDs), particularly alcohol abuse. However, the factors that mediate susceptibility to these conditions and the biological mechanisms that support these conditions are unclear. Stress-enhanced fear learning (SEFL) is a rodent model of stress exposure that captures the sensitization of fear learning seen in PTSD patients. In this dissertation I used the SEFL model to investigate the factors that govern stress susceptibility as well as the potential role of increased levels of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in supporting enhanced fear learning following stress.PTSD is twice as common in women compared to men, yet the vast majority of rodent studies investigating this condition have been conducted exclusively in males. In Chapter 1 I investigated sex differences in responses to an intense, acute stressor (15 footshocks over 90 minutes). I found that male and female rats showed similar changes in fear learning following stress, while some aspects of anxiety-related behavior were differentially impacted by stress. While levels of the GluA1 subunit of the AMPA receptor were altered within the basolateral amygdala (BLA) of male rats, no changes in GluA1 levels were observed in females. In Chapter 2 I demonstrated that a reduced severity stressor (4 footshocks over 90 minutes) revealed distinct susceptible and resilient groups in both male and female rats. Susceptible male and female rats showed increased fear and anxiety compared to their resilient counterparts. Some aspects of stress susceptibility manifested differently in males compared to females, with susceptibility associated with increased alcohol intake in males and increased baseline anxiety in females. In Chapter 3 I tested the role of Ca2+-permeable AMPA receptors in supporting changes in fear learning following stress. I found that neither overexpression of GluA1 nor genetic deletion of GluA2 was sufficient to enhance fear learning in the absence of stress. However, GluA2 deletion paired with prior footshock exposure enhanced subsequent fear learning in male mice but not females. Collectively, these findings indicate that while males and females show similar changes in fear learning following stress, these behavioral changes may be supported by different mechanisms. These results provide insight into the differential impacts of stress on behaviors relevant to PTSD symptomology across sexes.