Adult glucocorticoid receptor mRNA expression volatility in response to an acute stressor and juvenile CSF corticotropin-releasing factor: A pilot neurodevelopmental study. (24th April 2017) - Syed, Shariful A.
Highlights: The current pilot study in non-human primates has confirmed our hypothesis that juvenile CSF CRF, a marker of ELS, correlates significantly with a dynamic pattern of adult monocytic GR expression during an acute stress response. This study shows that monocytic GR mRNA expression reflects dynamic profile of cortisol release during stress, as well as a significant neurobiological measure correlate in CSF CRF. An ELS-associated allostatic adaptation suggests relative elevations of juvenile CSF CRF concentration set the stage for a relative hyperplasticity of GR expression in response to acute stress with potential long-term effects on HPA axis regulation and mood disorders. This study may be first to demonstrate reduction in peripheral GR expression as part of an acute stress response, which suggests that acute gene expression alterations contribute to the acute stress response. The current study suggests that, when studied dynamically, peripheral GR expression studies may be quite informative of the developmental trajectory of key central stress systems. Abstract: Introduction: Early life stress (ELS) has been shown to play a role in establishing persistent maladaptive HPA axis modifications that may contribute to the pathogenesis of mood and anxiety disorders. Central glucocorticoid receptor (GR) messenger RNA (mRNA) expression may facilitate (mal)adaptive responsivity to ELS. The role of adult monocytic GR mRNA expression, a putative CNS proxy, during acute stress exposure was explored as well as the ELS marker, juvenile cerebrospinal fluid (CSF) corticotropin-releasing factor. Methods: Six adult macaques (three of which were exposed to variable foraging demand, a form of ELS) underwent acute restraint. Baseline GR expression and plasma cortisol concentrations were separately measured followed by subsequent measurements following stress completion ( t = 0 min, 4 h, 5 days and 7 days). Juvenile CSF CRF concentrations were available in five subjects to determine their developmental association with GR expression in response to stress. Results: As expected acute restraint stress produced a significant increase in plasma cortisol concentrations most robustly observed at 4 h post-stress time point. There was a significant juvenile CSF CRF concentration x time interaction in predicting adult GR mRNA expression in response to stress (partial η 2 = 0.80). During acute stress juvenile CRF concentrations negatively predicted GR expression and during recovery, "flipped" to positively predict expression. Juvenile CSF CRF concentrations positively correlated with the volatility of adult GR mRNA expression. Conclusions: During acute stress, relatively high CSF CRF concentrations are associated with relatively rapid reductions in GR expression. Return to an ambient post-stress state was characterized by a direct relationship, consistent with increased HPA axis restraint in high CRF subjects. An ELS-associated allostatic adaptation suggests relative elevations of juvenile CSF CRF concentration set the stage for a relative hyper-volatility of adult GR mRNA expression in response to acute stress with potential long-term implications for HPA axis regulation.