Shifting the Stress Curve: Using Stress Inoculation and Exercise to Promote Resilience

Problem Stress influences an organism’s physiological systems via an inverted u-shaped curve: An optimum amount of stress will optimize body functions, but too little stress or too much stress for long periods of time can impair body functions. Researchers have been very interested in exploring the mechanisms that may “delay the tipping point” between the positive and negative effects of stress. A rightward shift in the stress curve would allow one to maintain optimal performance even at higher or more prolonged stress levels. The molecular and cellular mechanisms that underlie this rightward shift could result in resilience, clinically defined as the ability to endure stress without sustaining damage, or even to benefit from experiencing stress. The experiments described in this thesis investigate two potential mechanisms of resilience. The first mechanism is “stress inoculation,” in which previous exposure to a stressor “inoculates” an organism to respond more effectively to subsequent stressors. Recent studies suggest that controllable stress, even if the organism cannot predict when the stress will occur (thus called “unpredictable/controllable stress” or UST), may cause a rightward shift in the stress curve. The second mechanism is physical fitness that may improve the ability to cope with stress through molecular and cellular changes in the body. Method Experiment #1 (Stress inoculation): Thirty-three male Sprague-Dawley rats were in housing platforms for 21 days; 15 rats were exposed to unpredictable/controllable stress (UST), and 18 rats were not exposed to stressful stimuli as a control group. After 21 days, spatial memory and strategies were assessed on the Barnes maze under high stress conditions. Experiment #2 (Physical Fitness): A pilot study was conducted on 22 subjects (12 females, 10 males). Thirty human subjects (15 females, 15 males) were recruited among the freshmen taking HLED 120, Fit for Life, at Andrews University. Physical fitness was assessed with the MicroFit® FAS-2 system, a FDA-registered medical device. The students’ chronic stress levels were assessed with ICSRLE (Inventory of College Student Recent Life Experiences), and their depression and anxiety levels with DASS 21 (Depression Anxiety Stress Scale). Cognitive performance was assessed with two memory tasks: an object location task thought to be dependent on the hippocampus, and an n-back test thought to be dependent on the prefrontal cortex. Finally, the physiological stress response to the acute, cognitive stressors (performing the n-back test) was assessed by changes in salivary cortisol, heart rate, and systolic/diastolic blood pressure. Results Experiment #1: UST rats took less time to find the goal box on the Barnes maze (p\u3c0.05), and made fewer errors (p\u3c0.05) and repeat errors (p\u3c0.01). UST rats also took less time to find the goal box on reference memory trials (p\u3c0.05) and on working memory trials (p=0.05). After a new goal position was introduced, UST rats visited the previous goal position as their first error at a rate of 46.67%, while CT rats visited the previous goal position at a rate of 27.78%. UST used spatial strategies more frequently (p\u3c0.01) to find the goal box, while CT rats used random strategies more frequently (p\u3c0.01). Experiment #2 (Effects of physical fitness, stress, and depression and anxiety on memory): While higher fitness levels tended to be associated with better hippocampal memory scores (p=0.15, d=0.7), it did not affect prefrontal cortex-dependent memory (“n-back different”: p=0.286; “n-back same”: p=0.411. A significant, positive correlation was seen between ICSRLE and DASS 21 (p\u3c0.01). Higher levels of self-reported stress were not associated with worse hippocampal memory (p=0.389), but subjects with higher self-reports of depression/anxiety tended to have better hippocampal memory scores (p=0.075, d=0.8). Subjects with lower self-reported stress levels got higher “n-back different” scores than those with higher self-reported stress levels (p\u3c0.05), but no significant difference was found on “n-back same” memory scores between those two groups (p=0.898). Subjects with lower self-reports of depression/anxiety tended to get higher “n-back different” scores than those with higher self-reports of depression/anxiety (p=0.066, d=0.87). No significant difference was found between the “Top 50%” and “Bottom 50%” DASS 21 groups for “n-back same” memory scores (p=0.661). Conclusion Experiment #1 (Stress inoculation as an active resilience mechanism): The results of this study are consistent with the “stress inoculation hypothesis.” Exposure to unpredictable / controllable stress for 21 days causes “stress inoculation,” causing neural and behavioral adaptations that may represent a rightward shift of the stress curve. This would explain the optimal performance of UST with new environmental stressors on the Barnes maze. Experiment #2 (Physical activity as an active resilience mechanism): The results of this pilot study partially support the original hypotheses, but they indicate directions for future studies. First, more subjects should be added (at least 54) to validate the current statistical results. Second, more rigorous spatial memory tasks may be needed in order to avoid “ceiling effects.