Date of Award
Fall 2024
Document Type
Open Access Dissertation
Department
Biomedical Science
First Advisor
Aaron Jasnow
Abstract
The current studies were aimed to investigate two behavioral hallmarks of anxiety and stress-related disorders, avoidance responses and the over-generalization of fear. In the first set of studies, active avoidance and extinction learning, that parallels exposure therapy in preclinical rodent models, were used. It is known that stress can influence aversive learning and extinction training, which can result in poor extinction retention. However, it is not well understood how the stress response is facilitating extinction resistance in active avoidance learning across sexes. Therefore, the first set of studies aimed to investigate the role of biological sex and glucocorticoid receptor (GR) blockade in platform-mediated avoidance learning and extinction. There was a robust sex difference in the acquisition and extinction of avoidance responses where female mice displayed deficits in both. Following these results, GR blockade was used during learning in both males and females, where it was found that pairing GR antagonism during learning with extinction training resulted in reduced avoidance responses in females. Moreover, the current studies help to elucidate a mechanism for sex differences in active avoidance responses and highlight a role for the stress-response in mediating this sex bias. The second set of studies were designed to examine the role of the anterior cingulate cortex (ACC) in regulating the over-generalization of fear responses. It has previously been shown that the ACC regulates fear generalization during a recall test, however the role of the ACC during fear learning is not well understood. The current studies first examined mechanisms of memory encoding and consolidation within the ACC during strong contextual fear conditioning, that produces fear generalization 24-hours following learning. It was found that the ACC undergoes NMDA receptor dependent synaptic plasticity and consolidation. Next, circuit mechanisms were examined, where inputs from the basolateral amygdala (BLa) to the ACC were tested. BLa-to-ACC inputs were inactivated via inhibitory chemogenetics during learning and resulted in attenuation of generalized fear responses 24-hours later. Additionally, this circuit was tested in anxiety-like behavior using the open field and elevated plus maze, where it did not produce reliable effects. Finally, this circuit was tested for its sufficiency to produce context fear generalization using a weaker training protocol that does not produce it 24-hours later. BLa-to-ACC was activated via excitatory chemogenetics during learning, using the weak training protocol, 24 hours later mice showed significantly increased generalized fear expression. Overall, this set of studies showed that the ACC is a critical node in regulating generalized fear, where it encodes and consolidates information during learning. Moreover, the BLa-to-ACC projection is both necessary and sufficient to engage the ACC to form the generalized fear memory. Finally, the ventral hippocampus (vHPC) was examined, given its role in regulating contextual fear responses. vHPC was inactivated via inhibitory chemogenetics during learning that produces fear generalization 24-hours later, the results showed that vHPC activity is not necessary during learning to drive generalization the next day. Overall, these findings demonstrate that generalized fear memories are encoded within the ACC and further elucidate the circuit mechanisms that regulate generalized fear responses.
Rights
© 2025, Carly Vincent
Recommended Citation
Vincent, C.(2024). Sex Differences in Active Avoidance and Neural Circuit Mechanisms in Contextual Fear Generalization. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/8127