Despite the availability of many pharmaceutical therapies, Major Depression Disorder rates continue to rise--disproportionately so in women. The development of appropriate models is critical for the determination of behavioral phenotypes associated with the emergence of this debilitating disorder. Accordingly, the proposed research will investigate unique and novel approaches to the experimental examination of resilience that can be used to systematically evaluate susceptibility to the emergence of depression-like symptoms. Specifically, predisposed coping strategies and acquired contingency training [i.e., effort-based reward (EBR) training] will be explored to identify differential symptom expression in male and female rats.
In Specific Aim I, the effects of chronic stress on depression-like symptoms in animals with various predisposed coping strategies will be evaluated. Intended as a putative model of cognitive/behavioral training or therapy, in Specific Aim II, effort-based reward contingency training will be evaluated following exposure to chronic stress and a final learning challenge. In each Specific Aim, animals will be exposed to a probe trial simulating action/outcome discrepancies often associated with depression symptoms. Fos activation in various brain areas related to decision-making, action/outcome contingencies, emotional regulation, problem solving, stress, and motivation will be quantified along with markers of neuroplasticity and endocrinological markers of stress responsiveness. Microsequencing behavioral analysis will be conducted to determine relevant behavioral sequence disruptions during chronic stress and cognitive training, as well as responses to the action/outcome discrepancy in the final probe trial. In addition to traditional statistical analyses, multidimensional scaling analysis will be used as a more sophisticated statistical tool to determine key variables associated with effective coping and resilient phenotypes. In addition to having an opportunity to participate at all levels of the proposed research, in Specific Aim III, undergraduate students will have an opportunity to conduct research in a collaborating laboratory exploring optogenetic techniques directed toward the identification of more specific mechanisms of resilient responses. In sum, the proposed research will provide necessary resources for the PI to continue her work identifying unique rodent models to systematically investigate variables associated with depression and resilience phenotypes while simultaneously providing students with relevant and engaging research opportunities to prepare them for admission to neuroscience and biomedical graduate programs.
The proposed research provides a unique research approach addressing the high rates of depression that persist despite considerable research and ample neuropharmacological treatments available to the public. The models in this study take a more comprehensive approach to understanding Major Depression Disorder as predisposed coping strategies and behavioral contingency training in both males and females will be explored. Enhanced vulnerabilities related to chronic stress exposure and unexpected negative outcomes (action/outcome discrepancies)-- variables recognized as critical contributors to MDD in humans-- will be considered to understand more about core neurobiological phenotypes of this disorder.