Preclinical Models of Chronic Stress: Adaptation or Pathology?

Abstract

The experience of prolonged stress changes how individuals interact with their environment and process interoceptive cues, with the end goal of optimizing survival and well-being in the face of a now-hostile world. The chronic stress response includes numerous changes consistent with limiting further damage to the organism, including development of passive or active behavioral strategies and metabolic adjustments to alter energy mobilization. These changes are consistent with symptoms of pathology in humans, and as a result, chronic stress has been used as a translational model for diseases such as depression. While it is of heuristic value to understand symptoms of pathology, we argue that the chronic stress response represents a defense mechanism that is, at its core, adaptive in nature. Transition to pathology occurs only after the adaptive capacity of an organism is exhausted. We offer this perspective as a means of framing interpretations of chronic stress studies in animal models and how these data relate to adaptation as opposed to pathology.

Keywords: Allostasis; Animal model; Chronic social defeat; Chronic unpredictable stress; Stress inoculation; Stress resilience.

Figure 1.

From adaptation to pathology: progression of chronic stress. The y-axis reflects systems performance of the organism as a whole, and x-axis reflects net stress exposure (a product of stressor severity and/or chronicity of exposure). Following initiation of chronic stress, the organism enters into an adjustment period where behavior and physiology are modified in an attempt to meet the continuing challenge. For example, switching to conservative behavioral choices to limit exposure to danger and energy expenditure. Prolonged or intense stress exposure may eventually degrade systems performance and drive development of pathology, resulting in an adaptation failure which can be defined as a situationally inappropriate behavioral or physiological response (denoted by the gray shaded area)

Figure 2.

Individual differences in stress adaptation likely dictate the amount of stress exposure that can be tolerated. Reduced adaptative capacity (A) may be associated with early exhaustion of stress coping mechanisms, likely a product of gene X environment interactions. A reduced adaptive response (B) would cause more severe reactions fo stressors exposure, resulting in degraded systems performance but not frank pathology. Factors such as age or disease may effectively reduce the total reserve capacity of the organism (C), also resulting in enhanced pathological responses. Finally, in some cases response capacity may be enhanced (D), for example by exposure to stressors earlier in life.