NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE

本项目主要研究下丘脑神经元的调节机制， 和脑垂体功能之间的关系加压素（VP）增加 在PVN的小细胞神经元以及垂体VP中表达 (V1b)受体上调是增加的重要决定因素， 在几种慢性应激范式中观察到ACTH反应性。进一步 在辅助治疗期间的研究提供了VP重要性的证据， 诱导的大鼠关节炎，显示VP mRNA的升高， 小细胞PVN和垂体VP受体表达增加 下丘脑-垂体-肾上腺（HPA）轴显著激活。 垂体VP受体调节的研究扩展到 探讨V1 b受体表达的调控机制。 肾上腺切除导致VP结合和V1 b受体平行减少 mRNA，这种作用被糖皮质激素替代所阻止。 Brattleboro VP在肾上腺切除术后也有类似的变化 缺陷大鼠表明V1 b受体表达的减少是 不是由于肾上腺切除术诱导的小细胞VP增加。 大细胞分流术增加垂体暴露VP VP到垂体门脉循环引起垂体VP受体 下调而不改变V1 b受体mRNA水平。地塞米松 给药对V1 b受体mRNA无影响 程度.这些数据表明，V1 b受体mRNA水平直接影响着 受糖皮质激素或VP以外的下丘脑因子调节。 阐明应激诱导CRH受体机制的研究 在下丘脑室旁核（PVN）的作用集中在 糖皮质激素和神经通路。暂时性肾上腺切除术 诱导小细胞PVN CRH受体，糖皮质激素 给药或停药对应激诱导受体无影响 表情上行神经通路半切术 大鼠下脑干/脊髓投射神经元CRH受体mRNA的表达 PVN，但对基础或应激诱导的CRH受体mRNA没有影响 垂体营养小细胞亚群。这些数据显示 而来自脑干和脊髓的糖皮质激素和神经输入 脊髓影响CRH受体在PVN的表达，其他因素， 神经通路负责应激诱导的CRH受体 表情

This project has focused on the mechanism of regulation of hypothalamic and pituitary function during stress. Increases in vasopressin (VP) expression in parvicellullar neurons of the PVN, as well as pituitary VP (V1b) receptor upregulation are important determinants of the increased ACTH responsiveness observed in several chronic stress paradigms. Further evidence for the importance of VP was provided by studies during adjuvant induced arthritis in rats, showing elevation in VP mRNA in the parvicellular PVN and increases in pituitary VP receptors accompaning marked activation of the hypothalamic-pituitary-adrenal (HPA) axis. Studies on the regulation of pituitary VP receptors were extended to investigate the mechanism of regulation of V1b receptor expression. Adrenalectomy causes parallel decreases in VP binding and V1b receptor mRNA, an effect which was prevented by glucocorticoid replacement. Similar changes following adrenalectomy were found in Brattleboro VP deficient rats indicating that the decreased V1b receptor expression was not due to adrenalectomy-induced increases in parvicellular VP. Increasing pituitary exposure VP by surgical shunting of magnocellular VP to the hypophyseal portal circulation caused pituitary VP receptor downregulation without changes in V1b receptor mRNA levels. Dexamethasone administration in intact rats was without effect on V1b receptor mRNA levels. These data suggest that V1b receptor mRNA levels are directly regulated by glucocorticoids or by hypothalamic factors other than VP. Studies to elucidate the mechanism by which stress induces CRH receptors in the hypothalamic paraventricular nucleus (PVN) focused on the role of glucocorticoids and neural pathways. While adrenalectomy transiently induced CRH receptors in the parvicellular PVN, glucocorticoid administration or withdrawal had no effect on stress induced receptor expression. Surgical hemisections of ascending neural pathways induced CRH receptor mRNA in lower brainstem/spinal cord projecting neurons of the PVN, but had no effect on basal or stress-induced CRH receptor mRNA in hypophyseotrophic parvicellular subdivision. These data show that while glucocorticoids and neural imputs from the brain stem and spinal cord influence CRH receptor expression in the PVN, other factors and neural pathways are responsible for stress-induced CRH receptor expression.