Syed Shariful A, Smith Eric L P, Batuman Olcay, Rosenblum Leonard A, Owens Michael J, Nemeroff Charles B, Coplan Jeremy D
Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Psychiatry & Behavioral Sciences, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.
Division of Hematology/Oncology, Department of Internal Medicine, SUNY DMC, Brooklyn, NY, USA.
Neurosci Lett. 2017 Apr 24;647:20-25. doi: 10.1016/j.neulet.2017.03.017. Epub 2017 Mar 19.
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.
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=0min, 4h, 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.
As expected acute restraint stress produced a significant increase in plasma cortisol concentrations most robustly observed at 4h 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=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.
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.
早期生活应激（ELS）已被证明在建立持续的适应性不良的下丘脑-垂体-肾上腺（HPA）轴改变中起作用，这可能导致情绪和焦虑障碍的发病机制。中枢糖皮质激素受体（GR）信使核糖核酸（mRNA）表达可能促进对ELS的（适应不良）适应性反应。研究了成年单核细胞GR mRNA表达（一种假定的中枢神经系统替代指标）在急性应激暴露期间的作用，以及ELS标志物、青少年脑脊液（CSF）促肾上腺皮质激素释放因子。
六只成年猕猴（其中三只暴露于可变觅食需求，一种ELS形式）接受急性约束。分别测量基线GR表达和血浆皮质醇浓度，然后在应激结束后（t = 0分钟、4小时、5天和7天）进行后续测量。五名受试者可获得青少年CSF促肾上腺皮质激素释放因子（CRF）浓度，以确定其与应激反应中GR表达的发育关联。
正如预期的那样，急性约束应激导致血浆皮质醇浓度显著增加，在应激后4小时时间点观察到的最为明显。在预测应激反应中成年GR mRNA表达时，青少年CSF CRF浓度与时间存在显著交互作用（偏η = 0.80）。在急性应激期间，青少年CRF浓度与GR表达呈负相关，而在恢复期间，“翻转”为正相关。青少年CSF CRF浓度与成年GR mRNA表达的波动性呈正相关。
在急性应激期间，相对较高的CSF CRF浓度与GR表达的相对快速降低有关。恢复到应激后的环境状态的特征是一种直接关系，这与高CRF受试者中HPA轴抑制增加一致。一种与ELS相关的适应性负荷适应表明，青少年CSF CRF浓度的相对升高为成年GR mRNA表达在急性应激反应中的相对高波动性奠定了基础，这对HPA轴调节可能具有潜在的长期影响。
