Date of Award
Doctor of Philosophy
Matthew A. Cooper
Rebecca Prosser, Jim Hall, Kalynn Schulz, Keerthi Krishnan
The ventromedial aspect of the prefrontal cortex (vmPFC) is an evolutionarily conserved region of the frontal lobe with primary roles in social processing and emotional regulation. During particularly stressful situations, neurons of the vmPFC are recruited and, through dynamic circuit-based activity patterns, help the organism integrate pertinent sensory cues and act in a context-specific manner. In the dissertation that follows, I discuss investigations of vmPFC neural and immune system activity as they confer resilience and susceptibility, respectively, to the effects of acute social defeat stress in male Syrian hamsters. We have previously shown that vmPFC neural activity, as indexed by expression of the immediate early gene, cFos, is enhanced during acute social defeat stress in hamsters that have developed and maintained a dominant social status for 14 consecutive days. Dominant hamsters also display reduced social avoidance behavior following stress when compared with dominance status controls, supporting the claim that maintaining dominance is associated with stress resilience. On the other hand, subordinate hamsters are more susceptible to social defeat stress, as they reliably display elevated levels of social avoidance as well as reduced vmPFC cFos when compared with both dominance status controls and dominant counterparts. The claim that vmPFC neural activity is necessary for resilience to social defeat is bolstered by earlier reports that pharmacological inhibition of the vmPFC in dominant hamsters renders subordinate-like levels of social avoidance. Accordingly in Chapter 2, I present a study where I and colleagues sought to identify whether, during stress, dominant hamsters recruit a greater number vmPFC neurons that target the dorsal raphe nucleus (DRN), a stress effector region critical for the expression of social avoidance following social defeat stress. Results indicate that dominant hamsters recruit vmPFC-DRN projecting neurons to a greater degree than subordinate or control counterparts during stress. Moreover, subordinate hamsters showed no recruitment of this pathway during stress, as well as other neural activity within the vmPFC, when compared with non-stressed controls. In a follow-up study discussed in Chapter 3, I review experiments aimed at discerning whether acute social defeat leads to disruption of anatomical integrity in the vmPFC, particularly in socially subordinate hamsters. Results indicate that acute social defeat stress leads to cellular and synaptic degradation within the vmPFC and that these changes corresponded with increases in markers of proinflammatory activity in microglia and/or peripherally derived monocytes. Moreover, subordinate hamsters displayed increased markers of degeneration and microglia/monocyte activity within vmPFC, though there were no social status-dependent differences in synaptic densities. Finally, the stress-induced cellular degradation in the vmPFC was blocked with the antibiotic minocycline, which has been shown to reduce immune system activity. Taken together, the results of Chapter 3 implicate neuroimmune responses in acute stress-induced tissue degeneration in a social status-dependent manner. These projects collectively inform our understanding of neural mechanisms promoting and impeding stress processing within the vmPFC. Accordingly, the results from this dissertation may inform future studies focused on the cellular mechanisms of stress resilience as well as provide potential targets for pharmacotherapeutic treatments promoting resilience to acute traumatic stress.
Grizzell, Johnathon, "Roles for the Ventromedial Prefrontal Cortex in Resistance to Acute Social Stress. " PhD diss., University of Tennessee, 2019.