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The hypothalamus–pituitary–adrenal axis is the main physiological stress response system and regulating the release of cortisol. The two corticoid receptors encoded by the genes NR3C1 and NR3C2 are the main players in regulating the physiological response to cortisol. This biological system has been linked to neurocognitive processes and memory, yet the mechanisms remain largely unclear. In two independent general population studies (SHIP, total sample size > 5500), we aim to diseantangle the effects of genetic variation, gene expression and cortisol on verbal memory and memory associated brain volume. Especially for NR3C1 results exhibited a consistent pattern of direct an interactive effects. All three biological layers, genetic variation (rs56149945), gene expression for NR3C1 and cortisol levels, were directly associated with verbal memory. Interactions between these components showed significant effects on verbal memory as well as hippocampal volume. For NR3C2 such a complex association pattern could not be observed. Our analyses revealed that different components of the stress response system are acting together on different aspects of cognition. Complex phenotypes, such as cognition and memory function are regulated by a complex interplay between different genetic and epigenetic features. We promote the glucocorticoid receptor NR3C1 as a main target to focus in the context of verbal memory and provided a mechanistic concept of the interaction between various biological layers spanning NR3C1 function and its effects on memory. Especially the NR3C1 transcript seemed to be a key element in this complex system.
Objective
Alexithymia is associated with various mental and physical disorders. Some rare evidence also suggested high alexithymia to affect the HPA axis based on small and selective samples. It was aimed to investigate the impact of alexithymia on basal cortisol levels in a large population-based cohort.
Methods
In a sample of N = 3444 individuals from the Study of Health in Pomerania (SHIP-TREND-0), the effect of alexithymia on basal serum cortisol levels was investigated in a cross-sectional design.
Multiple linear regressions utilizing cortisol levels as the response variable and alexithymia as the predictor of interest were calculated, while adjusting for conven-tional confounding covariates including depression. Multiple stratified, moderation and mediation analyses were performed to validate the results.
Results
Alexithymia was not significantly associated with basal cortisol levels (b = 0.23, 95 percent confidence interval (CI) of [-0.24, 0.69]; sr2 = 0.00, CI: [-0.00, 0.00]).
Sex- and age-stratified regression analyses as well as dichotomized models of non-alexithymic and alexithymic individuals substantiated the non-significance.
Additional mediation analyses with (1) depression and (2) physical health (R2 > 1 in both cases) and moderation analysis regarding the interaction of physical health and alexithymia (b = -1.45, 95 percent confidence interval (CI) of [-6.13, 3.32]; sr2 = 0.00, CI: [-0.00, 0.00]) corroborated the results.
Conclusion
This study does not support previous findings as it shows no association between alexithymia and basal cortisol; however, a consideration of the circadian rhythm, stress exposure or specific sample compositions heeding the methodological design should be the subject of further research.