Defense Date

2021

Document Type

Thesis

Degree Name

Master of Science

First Advisor

Gretchen Neigh

Abstract

Anxiety disorders disproportionately impact women and are more prevalent in people with a history of chronic stress. Post-traumatic stress disorder (PTSD) is a type of stress and trauma-related disorder that is largely characterized by hyperarousal to fear-based cues. The inability to dissociate the fear-response from a non-threatening cue is known as impaired safety learning. Given that N-methyl-D-aspartate (NMDA) receptors are key mediators of learning behaviors, we examined the role of NMDAr function in deficient safety learning. Previous studies have shown that female rats with a history of stress have altered NMDAr gene expression and altered glutamatergic signaling; therefore, we hypothesized that alterations in NMDAr function in females with chronic adolescent stress accompanies the safety learning deficit they may exhibit as adults. To test this hypothesis, we exposed male and female rats to a mixed modality stress paradigm during adolescence. The mixed modality stress paradigm consists of repeated restraint, social defeat, and individual housing. Once in adulthood all animals were subjected to a fear conditioning procedure designed to test the ability of safety learning. For the fear conditioning procedure, we measured the rat’s startle response to a light cue that had been previously paired with a shock stimulus. Following extinction of the learned behavior, we tested safety learning by presenting the previously shock-associated cue with an acoustic startle probe. Females with a history of stress showed impaired safety learning by a failure to demonstrate reduced responses to the new association of the light to absence of shock. A separate cohort of rats were treated with the NMDAr agonist D-cycloserine (DCS) that has been shown to enhance fear extinction learning. Females treated with DCS that had a history of stress showed improved safety learning compared to the females who also had a history of chronic stress but did not receive DCS, suggesting that modulation of NMDA receptors can restore safety learning in females with a history of chronic adolescent stress. Males showed no difference between stress groups and non-stressed groups with the addition of DCS. The NMDAr subunit implicated in fear acquisition, NR2B, was shown to be present in equal quantities in both males and females of non-stressed (NS) and chronic adolescent stress (CAS) condition in the basolateral amygdala. However, in the central amygdala CAS males and females both had significantly less NR2B than their NS counterparts. These data suggest that chronic stress during adolescence modifies NMDA receptor function in a manner associated with impairments in learning through alterations in the NR2B subunit in the central amygdala. A better understanding of the mechanisms underlying stress-induced impairments in fear behaviors and safety learning will provide a foundation to examine alternative therapies for people living with fear-based disorders like PTSD.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-7-2021

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