Date of Award

8-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Psychology

Major Professor

Matthew A. Cooper

Committee Members

Helen A. Baghdoyan, Gordon M. Burghardt, Subimal Datta, Rebecca A. Prosser

Abstract

Stress is a contributing factor in the etiology of several mood and anxiety disorders, and animal models of social defeat have been used to investigate the biological basis of stress-related psychopathologies. Syrian hamsters are highly aggressive and territorial, but after social defeat they exhibit a conditioned defeat (CD) response which is characterized by increased submissive behavior and a failure to defend their home territory against a smaller, non-aggressive intruder. We have previously shown that dominant male hamsters show increased c-Fos expression in the infralimbic (IL) subdivision of the ventromedial prefrontal cortex (vmPFC) following social defeat and display a reduced CD response at testing compared to subordinates and controls. Pharmacological inactivation of the vmPFC prevents resistance to CD in dominants, suggesting that neural activity in the vmPFC is necessary for CD resistance. In this dissertation, we tested the overarching hypothesis that dominant hamsters have a distinct pattern of neuronal activity and neurochemical responses within the vmPFC that facilitate resistance to CD. Specifically, we predicted that dominant hamsters will display a distinct neurochemical profile in the vmPFC and activate an IL neural projection to the basolateral amygdala (BLA) during social defeat. Furthermore, we predicted that selective activation of an IL-to-BLA neural projection during social defeat is sufficient for resistance to CD. Using a technique called untargeted metabolomics, we found that a distinct neurochemical profile in the vmPFC is associated with stress resilience. Specifically, dominant hamsters had elevated levels of tyrosine and methionine in the vmPFC following social defeat. Next, we co-localized a retrograde tracer, cholera toxin B, and c-Fos and identified neural projections from both the IL and prelimbic (PL) subdivisions of the vmPFC to the BLA that are activated by dominants during social defeat. Finally, we show that selective activation of an IL-to-BLA neural projection using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) is sufficient to promote resistance to CD in subordinate and social status control hamsters. This project extends our understanding of the neurochemical profiles and neural circuits underlying stress resilience, which is an important step towards delineating a circuit-based approach for the prevention and treatment of stress-related psychopathology.

Comments

Portions of this document were previously published in journal "Neurobiology of Stress"

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