ABR: Melding Mathematical and Theoretical Models of Stress

Tufts University, Medford MA

Investigators

Abstract

Non-technical Abstract The stress response is a major mechanism of resilience. However, even after nearly 100 years of studying stress we still lack a rigorous predictive model that allows us to know what the impact of stressors on individuals and populations might be. The lack of such a model is a long-standing roadblock to our understanding of the ecology and pathophysiology of stress responses. This project will create and test the first quantitative predictive model of stress pathophysiology. The foundation will be the Reactive Scope Model, a graphical model of stress. A central component of this graphical model is that prolonged activation of a stress response creates wear-and-tear. Here a mathematical model of stress based upon wear-and-tear will be constructed and integrated with laboratory studies using captive birds as models. Overall, the project will generate a new predictive quantitative model for how individuals, and by extension populations of individuals, will respond to stressors. The creation of an integrated conceptual and quantitative theory will provide the foundation to resolve long-standing questions in stress physiology and open up novel areas of research. This project will provide training of students at all levels. Specific activities will recruit women and minority students to research positions. Cross-disciplinary training will teach these students how to integrate physiological and quantitative techniques. A weekly research blog by research students will incorporate the research into an introductory Endocrinology class, thereby providing a research focus to a lecture class. The work will be disseminated through publications in the research literature and presentations to the general public. Technical Abstract The quantitative model will consist of a system of nonlinear partial differential equations that captures the dynamics of the Reactive Scope conceptual model. Using two established stress and stress response protocols, introduction to captivity and rotating intermittent stressors applied to captive birds, numerical solutions to deterministic approximations suggested by the Reactive Scope model will be tested against empirical experimentation. The key goal will be to understand the temporal dynamics of wear-and-tear. Predicted timing and effects of an individual bird's responses to wear-and-tear will be assessed in four ways: alterations in glucocorticoid function by measuring plasma hormone concentrations and glucocorticoid receptor dynamics; attenuation of sympathetic nervous system responses by measuring heart rate and heart rate variability; changes in behavior by measuring overall activity levels and responses to novel objects; and increases in homeostatic instability by measuring DNA damage as evidenced by changes in telomere length and cellular DNA fragmentation. The laboratory results will guide iterative alterations to the quantitative model, indicate new experimental designs based upon the updated quantitative model, and form revised predictions for subsequent laboratory tests of stress and wear-and-tear.