Department of Psychology and Neuroscience, University of Colorado, UCB 345, Boulder, CO 80309, USA.
J Neuroendocrinol. 2011 Dec;23(12):1241-51. doi: 10.1111/j.1365-2826.2011.02220.x.
The negative-feedback actions of corticosterone (CORT) depend on both phasic and tonic CORT secretion patterns to regulate hypothalamic-pituitary-adrenal (HPA) axis activity. How these two different CORT secretion pattens influence specific intracellular signal transduction pathway activity within the cellular elements of the HPA axis has not been determined. For example, it is unknown whether CORT has suppressive actions over signal transduction events within medial parvocellular paraventricular nucleus (PVN) corticotrophin-releasing hormone (CRH) neurones, nor whether these suppressive actions are responsible for alterations in PVN transcriptional processes and neurohormone secretion associated with stress. The extracellular-regulated kinase (ERK) is a stress activated intracellular signalling molecule that is potentially subject to glucocorticoid negative-feedback regulation. We tested the ability of CORT to modulate levels of the active (phosphorylated) form of ERK (pERK1/2) in the PVN of rats. Acute psychological stress (restraint) produced a rapid increase in the number of PVN pERK1/2 immunopositive cells within CRH neurones. Absence of tonic CORT via adrenalectomy (ADX) produced no change in basal pERK1/2 cell counts but augmented the increased pERK1/2 cell counts elicited by acute restraint. Treatment of ADX rats with CORT in the drinking water normalised this enhanced pERK1/2 response to stress. By contrast, treatment of ADX rats with a phasic increase in CORT 1 h before restraint had no effect on pERK1/2 cell counts, despite substantially suppressing stress-induced PVN crh gene expression and adrenonocorticotrophic hormone secretion. This tonic CORT inhibition of stress-induced activation of ERK1/2 may involve both alteration of the activity of stress-dependent neural inputs to PVN CRH neurones and alteration within those neurones of stress-dependent intracellular signalling mechanisms associated with ERK activation.
皮质酮（CORT）的负反馈作用取决于 CORT 的时相和基础分泌模式，以调节下丘脑-垂体-肾上腺（HPA）轴的活性。这两种不同的 CORT 分泌模式如何影响 HPA 轴细胞成分中的特定细胞内信号转导途径的活性尚未确定。例如，尚不清楚 CORT 是否对内侧小细胞室旁核（PVN）促肾上腺皮质激素释放激素（CRH）神经元中的信号转导事件具有抑制作用，也不知道这些抑制作用是否负责与应激相关的 PVN 转录过程和神经激素分泌的改变。细胞外调节激酶（ERK）是一种应激激活的细胞内信号分子，可能受到糖皮质激素的负反馈调节。我们测试了 CORT 调节大鼠 PVN 中 ERK（pERK1/2）的活性（磷酸化）形式水平的能力。急性心理应激（束缚）导致 CRH 神经元中 PVN pERK1/2 免疫阳性细胞数量迅速增加。通过肾上腺切除术（ADX）消除基础 CORT 不会改变基础 pERK1/2 细胞计数，但会增强急性束缚引起的 pERK1/2 细胞计数增加。用饮用水向 ADX 大鼠给予 CORT 治疗可使这种增强的应激 pERK1/2 反应正常化。相比之下，在束缚前 1 小时给予 ADX 大鼠时相性增加的 CORT 处理对 pERK1/2 细胞计数没有影响，尽管它大大抑制了应激诱导的 PVN crh 基因表达和促肾上腺皮质激素分泌。这种基础 CORT 对应激诱导的 ERK1/2 激活的抑制作用可能涉及改变应激对 PVN CRH 神经元的神经传入的活性，以及与 ERK 激活相关的应激依赖性细胞内信号机制的改变。
