Text

theses

Despite stress-associated disorders having a higher incidence rate in females, historically preclinical research in rodents mainly utilizes males. Rodent chronic stress paradigms, such as chronic social defeat and chronic corticosterone administration, were mainly designed and validated in males and subsequent attempts to use these paradigms in females has demonstrated sex differences in the behavioral and HPA axis response to these stressors. We evaluated the behavioral and neuroendocrine response to two novel social stress paradigms, social instability stress (SIS) and chronic non-discriminatory social defeat stress (CNSDS). SIS exposes adult mice to unstable same-sex social hierarchies for 7 weeks. The CNSDS model, a modified social defeat protocol, simultaneously introduces male and female C57BL/6J mice into the home cage of resident CD-1 aggressors for 10 daily 5-minute sessions, with CD-1 aggressors attacking males and females indiscriminately. In the CNSDS paradigm, stress resilient (RES) and susceptible (SUS) subpopulations emerge in both sexes, with SUS mice displaying increased negative valence behaviors relative to RES and control mice in both sexes. SUS male and female mice also displayed hypothalamus-pituitary-adrenal (HPA) axis activation following CNSDS exposure. SIS effectively induces negative valence behaviors and HPA axis activation in both males and females. Additionally, the effects of SIS on negative valence behaviors are reversed by chronic antidepressant treatment with fluoxetine (FLX) in both males and females.

Chronic stress paradigms in rodents also permit the study of antidepressant treatment resistance. Inhibition of mature Dentate Gyrus (DG) granule cells, through both cell autonomous Gi-coupled receptors and the local microcircuitry, may be critical for mounting a behavioral response to antidepressants. The novelty-suppressed feeding (NSF) task allows us to behaviorally assess response status because a bimodal distribution emerges within the stress+FLX groups. Responders to FLX have a shorter latency to eat the pellet within the brightly light center of the NSF arena than non-responders. We observe that non-responders to FLX have more DG activation and less hippocampal neurogenesis. Additionally, DREADD mediated inhibition of the ventral DG results in a decrease in negative valence behaviors. Interestingly, non-responders to FLX are converted into responders following DREADD mediated inhibition of the ventral DG. Results from these projects can further our understanding of the involvement of the DG in response to stress and antidepressant response.

ETD_10802

Ph.D.

Includes bibliographical references

doi:10.7282/t3-apr8-4154

ETD doctoral

The author owns the copyright to this work.