The parametric determinants of heterogeneity in the behavioral and neurobiological impact of stress.

Exposure to traumatic stress can lead to a wide range of persistent, deleterious biological and behavioral effects. Despite a significant national investment of resources directed toward both basic and clinical stress research, the field has come up short in the development of effective treatments for stress disorders. One potential explanation for this discrepancy is a lack of field-wide procedural and theoretical cohesion. There are a great number of different stress procedures used by basic research scientists and yet there has been no attempt to comprehensively consolidate findings across stressors. For example, we have previously shown that giving a rat access to a glucose solution following stress exposure alleviates the deleterious effects of stress. However, the effects of post-stress glucose have yet to be tested outside of this specific stress procedure. We have hypothesized that differences in the dimensions of stress exposure (such as quality, volume, and chronicity of the stressor) may in part account for the biological and behavioral heterogeneity of stress disease. Here, we test this hypothesis. In the second chapter of this dissertation, we assess the physiological impacts of post-stress glucose in order to better understand its potential mode of action. In a series of experiments, we found that glucose may be alleviating the negative sequelae of stress exposure by helping the organism maintain energetic homeostasis. The study also rules out a corticosterone-mediating mechanism of action for glucose’s prophylactic effects. In the third chapter of this dissertation, we examine the behavioral and biological effects of stress procedures with very different stress volumes (as defined by shock length x intensity x number). We found that stress volume counter-intuitively impacts the resultant behavior and neurobiology. Namely, we found that high-volume stress does not produce stress-enhanced fear learning (SEFL), a quintessential effect of moderate-volume stress. However, when rats exposed to high-volume stress were given glucose, SEFL behavior appeared. We identify a few behavioral and biological differences that provide a potential mechanism of the effect. These studies suggest that the volume of the stressor has a clear impact on the resultant disease phenotype and intervention efficacy. In the fourth chapter, we examine the effects of a different stress dimension: chronicity. We found that stress chronicity impacts the resultant behavior and neurobiology in an additive way. Namely, we found that chronic stress appears to produce the same non-associative enhancements of fear quintessential to the acute stressor, plus a unique associative component. We provide evidence for this conclusion through several behavioral and neurobiological means. These studies suggest that the chronicity of the stressor can impact the mechanism and severity of disease. Finally, all of the above findings are discussed in terms of their implications in the stress field