miRNA与CRF受体亚型调控应激相关障碍易感性

Exposure to stressful event during development has consistently been shown to produce long-lasting alternations in the hypothalamic-pituitary-adrenal (HPA) axis, which changes stress response/ resilience in adults and increase the risk of mental disorders. In the previous study, we found that stress exposure in childhood alters the CRF1 and CRF2 expression in brain, inhabits HPA axis response and increases stress susceptibility. Further more, chronic stress in adult also changes stress susceptibility which related to the function of HPA axis, hippocampus and prefrontal cortex. While aerobic exercise could recover the dysregulated HPA axis function, abnormal stress compliance and behavior. The study showed that exercise had protective effection and the protective effection was superior to receptor antagonist. The present study will build post-traumatic disorder model and hypoactivated HPA axis model in juvenile and adult animals, assess the behavior changs ( anxiety and depression, learning and memory), detect expression of CRF and CRF1mRNA, CRF2mRNA, and miRNA-124a, miRNA-18a in hypothalamus, hippocampus, amygdale, prefrontal cortex, raphe dorsal nucleus.The aim is to identify the effects of CRF and CRF1 and CRF2 expression and their arrange in cells, miRNA-124a and miRNA-18a on stress resilience and vulnerability to stress related mental disorder.

发育期应激经历改变HPA轴功能，影响应激顺应性，增加心理障碍易感性。我们发现，幼年期应激经历可长期抑制HPA轴功能，改变应激反应。其原因可能是应激改变了中枢CRF受体亚型的分布与表达。成年动物慢性应激后的应激顺应性也发生变化，这一变化与HPA轴、海马和前额叶皮质功能相关。而递增性有氧运动可改善应激顺应性和行为异常，对海马、前额叶皮质和行为具有保护作用，其效果优于受体拮抗剂。本研究以创伤后应激障碍动物模型和外源性皮质酮致HPA轴功能抑制动物模型为研究对象，观察幼年和成年期创伤性应激对HPA轴功能，焦虑、抑郁、学习与记忆障碍的影响，及与中枢关键脑区CRF及其受体CRF1mRNA、CRF2mRNA表达和miRNA-124a和miRNA-18a表达的关系。证明miRNA-124a和miRNA-18a，CRF及其受体亚型表达与分布是否是应激顺应性和应激相关障碍易感性的初始靶点。

研究提示，发育期应激经历改变HPA轴功能，影响应激顺应性，增加心理障碍易感性，其原因可能是应激改变了中枢CRF受体亚型的分布与表达；成年动物慢性应激后的应激顺应性也发生变化，这一变化与HPA轴、海马和前额叶皮质功能相关，但精确机制不清。本研究以创伤后应激障碍动物模型，慢性不可预期性应激致抑郁动物模型和外源性皮质酮致HPA轴功能抑制动物模型为研究对象，聚焦早年应激经历致应激相关障碍易感性的机制。研究系统观察了模型动物焦虑、抑郁、学习与记忆；HPA轴功能，中枢关键脑区CRF及其受体CRF1、5-HT受体亚型、GR及其分子伴侣FKBP5、GABAAR亚型，及相关miRNA表达的变化。发现早年应激经历改变CRF及其受体亚型表达与分布，导致GR表达下降和FKBP5表达升高，5-HT1AR和5-HT2CR表达改变，以及GABAAR γ2，α2 和α5亚基区域特异性改变。提示上述指标与应激相关障碍易感性密切相关。研究还发现，早年应激经历改变表观遗传学指标miR-34c、miRNA-135a、miRNA-16、miR-124a和miR-18a在中枢特定脑区的表达。从而确定了特定miRNA和CRFR1是应激顺应性和应激相关障碍易感性的初始靶点；特定miRNA和杏仁核GR表达下降，FKBP5表达增多，海马和前额叶5-HT1AR和5-HT2CR表达改变以及中枢关键脑区GABAAR γ2，α2 和α5亚基特异性变化参与早年应激经历致应激相关障碍易感性改变。在干预方法上，研究发现，CRFR1、CR受体拮抗剂、盐酸帕罗西汀、氯硝西泮和长期规律运动均可改善早年应激和成年期模型动物行为学指标、改善神经递质受体的表达、HPA轴功能、中枢CRFR1和GR表达。但长期规律运动具有无创性的优势，提示其可作为改善PTSD症状、稳定HPA轴功能和降低应激相关障碍易感性的干预方法。