REGULATORY CHANGES IN NEUROENDOCRINE STRESS INTEGRATIVE CIRCUITRY PRODUCED BY A VARIABLE STRESS PARADIGM
REGULATORY CHANGES IN NEUROENDOCRINE STRESS INTEGRATIVE CIRCUITRY PRODUCED BY A VARIABLE STRESS PARADIGM
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DOI：
10.1159/000126839
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发表时间：
1995-02-01
影响因子：
4.1
通讯作者：
PREWITT, C
中科院分区：
文献类型：
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作者：
HERMAN, JP;ADAMS, D;PREWITT, C
应激是对调节体内平衡的神经内分泌系统的一种复杂刺激。总的来说，应激效应是由下丘脑室旁核（PVN）内侧小细胞区的应激整合促肾上腺皮质激素释放激素（CRH）神经元介导的。这些神经元汇总了大量的神经元和激素信号，最终产生生理上有意义的循环糖皮质激素水平。在本实验中，我们研究了一个慢性可变的压力范例的影响，促肾上腺皮质激素（ACTH）促分泌素的生物合成的PVN和肾上腺皮质类固醇受体的mRNA表达在海马结构，PVN和皮质的指数。可变应激者范式产生与慢性应激一致的综合征，包括皮质酮、ACTH和催乳素的基线分泌过多以及肾上腺肥大。PVN中CRH mRNA水平增加约61%，与观察到的下丘脑-垂体-肾上腺（HPA）上调一致。精氨酸加压素（AVP）mRNA的表达在个别小细胞PVN神经元（16%）有一个小的，但显着的增加，并没有明显增加的AVP mRNA含有神经元的数量。大细胞PVN、视上核或视交叉上核中AVP表达无变化。总之，这些数据突出了CRH在面对长期挑战时维持HPA上调的重要性。为了研究慢性应激对糖皮质激素受体调节的影响，评估了海马、额顶叶皮质和PVN中盐皮质激素受体（MR）和糖皮质激素受体mRNA的表达。慢性应激显著下调海马CA 1、CA 3和齿状回MR mRNA表达，下调海马CA 1、齿状回和额顶叶GR mRNA表达。受体生物合成的减少表明应激在基因组水平上调节糖皮质激素对海马细胞生理学的影响的能力，可能影响从认知到HPA轴反馈调节的过程。在小细胞PVN水平，GR mRNA表达下降至对照值的60%。GR mRNA表达与室旁核CRH mRNA表达呈负相关，表明室旁核水平上CRH基因表达升高与GR下调之间存在相关性。
Stress represents a complex stimulus to neuroendocrine systems regulating homeostasis. By and large, stress effects are mediated by stress-integrative corticotropin-releasing hormone (CRH) neurons present in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons summate a large variety of neuronal and hormonal signals to eventually yield a physiologically meaningful level of circulating glucocorticoids. In the present experiments, we examined the effects of a chronic variable-stresser paradigm on indices of adrenocorticotropic hormone (ACTH) secretagogue biosynthesis in the PVN and adrenocorticosteroid receptor mRNA expression in the hippocampal formation, PVN and cortex. The variable-stresser paradigm produces a syndrome consistent with chronic stress, including baseline hypersecretion of corticosterone, ACTH and prolactin, and adrenal hypertrophy. CRH mRNA levels in the PVN are increased some 61%, consistent with the observed hypothalamo-pituitary-adrenal (HPA) up-regulation. There was a small but significant increase in arginine vasopressin (AVP) mRNA expression in individual parvocellular PVN neurons (16%), and no demonstrable increase in the number of AVP mRNA-containing neurons. No change in AVP expression was seen in the magnocellular PVN, supraoptic or suprachiasmatic nuclei. In all, these data highlight the importance of CRH in maintaining HPA up-regulation in the face of prolonged challenge. To investigate effects of chronic stress on the regulation of glucocorticoid receptivity, mineralocorticoid receptor (MR) and glucocorticoid receptor mRNA expression was assessed in the hippocampus, frontoparietal cortex and PVN. Chronic stress significantly down-regulated MR mRNA expression in subfields CA1, CA3 and the dentate gyrus (DG), and GR mRNA expression in subfields CA1, the DG and frontoparietal cortex. The reduction in receptor biosynthesis suggests the capacity for stress to modulate the impact of glucocorticoid on hippocampal cell physiology at the genomic level, potentially influencing processes ranging from cognition to feedback regulation of the HPA axis. At the level of the parvocellular PVN, GR mRNA expression was decreased to 60% of control values. GR mRNA expression was negatively correlated with PVN CRH mRNA expression, suggesting a relationship between elevated CRH gene expression and down-regulation of GR at the level of the PVN.