Studies on molecular mechanisms underlying posttraumatic stress disorder (trauma)

本研究涉及与创伤后障碍危机相关的分子机制的评估，创伤后障碍常见于处于严重应激环境中的受试者。患者会回忆起他们在几个月后和几年后的紧张经历。这可能涉及到通过在大脑基因转录水平上调节特定目标蛋白的从头合成来长期巩固瞬时信号。转录因子是一种核蛋白，与特定的核心核苷酸序列具有高亲和力，调节RNA聚合酶II的活性，该聚合酶II负责从细胞核中的基因组DNA形成mRNA。动物受到不同时期的冷应激和束缚应激，然后解剖离散的中心和外围结构，然后制备核提取液，以确定不同转录因子的DNA结合活性。激活蛋白-1(AP1)和环磷酸腺苷反应元件结合蛋白(CREB)在大鼠下丘脑、垂体和肾上腺中的DNA结合活性显著增加，而在大脑新皮质、海马和纹状体中则无明显变化。相比之下，冷应激和束缚应激导致小鼠海马齿状回颗粒层5-溴脱氧尿苷(BrdU)免疫反应阳性细胞形成的簇数显著减少。这些结果表明，严重的应激状态会通过大脑中转录因子对基因表达的调节而导致成年神经发生的减弱。寻找靶基因对于人类创伤后精神障碍的治疗无疑具有重要意义。

The present study deals with evaluation of molecular mechanisms associated with crisis of the posttraumatic disorder often seen with subjects in severe stressful situations. Patients would recall the stressful experience they had before months and years later. This could involve long-term consolidation of transient signals through modulation of de novo synthesis of particular target proteins at the level of gene transcription in the brain. Transcription factors are nuclear proteins with high affinity for a particular core nucleotide sequence to modulate the activity of RNA polymerase II that is responsible for the formation of mRNA from genomic DNA in the nucleus. Animals were subjected to cold and immobilization stress for different periods, followed by dissection of discrete central and peripheral structures and subsequent preparation of nuclear extracts for determination of DNA binding activity of different transcription factors. A marked increase was seen in DNA binding activities of activator protein-1(AP1) and cyclic AMP responsive element binding protein (CREB) in the rat hypothalamus, pituitary and adrenal glands, but not in the cerebral neocortex, hippocampus and striatum. By contrast, cold and immobilization stress induced a significant decrease in the number of clusters formed by cells immunoreactive to 5-bromo-deoxyuridine(BrdU) in the granular layer of the dentate gyrus in mouse hippocampus. These results suggest that severe stressful situation would lead to attenuation of adult neurogenesis through modulation of gene expression by transcription factors in the brain. Search for the target genes is undoubtedly of great importance for the therapy and treatment of posttraumatic disorder in human beings.