Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces.

The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health. We recently reported that 5HTTLPR modulates cortisol response in healthy military men exposed to intense stress. Less is known of its combined effects with environmental factors in this context, or of its effect on neuroprotective stress responses. In this follow-up study, we examined the unique and combined effects of 5HTTLPR and prior trauma exposure on neuroprotective (salivary nerve growth factor [sNGF]), anabolic (dehydroepiandrosterone sulfate [DHEAS] and testosterone), and catabolic (cortisol) stress responses. Ninety-three healthy, active-duty military men were studied before, during, and 24h after a stressful 12-day survival course. Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated, after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior trauma exposure demonstrated counterbalancing (additive) forces. Similar patterns were found for DHEAS. To our knowledge, this study is the first to report counterbalancing genetic and environmental effects on novel biomarkers related to resilience in humans exposed to real-world stress. These findings have profound implications for health, performance and training in high-stress occupational settings.

Neuroprotective-neurotrophic effect of endogenous dehydroepiandrosterone sulfate during intense stress exposure.

Recent reports demonstrate neurotrophic properties of dehydroepiandrosterone sulfate (DHEAS) in men at rest, as well as profound neurotrophic responses to stress in both men and women. Little is known of neuroprotective-neurotrophic effects of DHEAS during stress exposure, either in men or women. This translational study was designed to examine neuroprotective-neurotrophic effects of DHEAS throughout intense stress exposure in healthy men and women. The study took place within a stressful 12-day military survival course. Utilizing a longitudinal cross-sectional repeated measures design, One hundred sixteen healthy active-duty military personnel (80% male) were studied before, during, and 24h after the course. The dependent variable was the neurotrophin salivary nerve growth factor (sNGF). In terms of total hormone output, the effect of DHEAS on sNGF was mediated by testosterone. Unlike testosterone or cortisol, DHEAS reliably predicted sNGF at each time point, and change in DHEAS predicted change in sNGF across time points. Baseline DHEAS predicted total sNGF output across the stress trajectory. Consistent with preclinical as well as cross-sectional human research, this study demonstrates neuroprotective-neurotrophic effects of DHEAS in healthy men and women exposed to intense stress. Results are evaluated in relation to established criteria for causation.

Salivary nerve growth factor response to intense stress: effect of sex and body mass index.

Ample evidence links stress to psychiatric and neurological disease. Although many studies examine stress hormone secretion and receptor activity, exciting new developments signify a shift in focus to neuromodulatory systems influencing neuronal development, survival, and neuroplasticity. The purpose of this study was to characterize salivary nerve growth factor (sNGF) responses to intense stress exposure in healthy military members undergoing survival training. A second purpose was to explore effects of age, sex, education, and body mass index (BMI). One hundred sixteen military members (80% male) were studied before, during, and 24 h after a stressful mock-captivity exercise. sNGF was measured at all three time points. Reactivity, recovery, and residual elevation of sNGF were computed. General linear modeling with repeated measures evaluated effect of stress exposure, as well as the roles of age, sex, education, and BMI. sNGF increased 137% from baseline to intense stress. During recovery, sNGF remained elevated an average of 67% above baseline (i.e., residual elevation). Men showed greater sNGF reactivity than women quantified by larger absolute T1-T2Δ (+148.1 pg/mL vs. +64.9 pg/mL, p<0.017). A noteworthy trend of higher sNGF concentrations in low BMI participants was observed (p=0.058). No effects of age or education were shown. This study shows substantial reactivity and residual elevation of sNGF in response to intense stress exposure in healthy humans. Further research is needed to refine the sNGF assay, fully characterize the sNGF stress response, delineate correlates and mechanisms, and validate therapeutic applications.