Makino Shinya, Tanaka Yasushi, Nazarloo Hossein Pournajafi, Noguchi Tohru, Nishimura Kanae, Hashimoto Kozo
Second Department of Internal Medicine, Kochi Medical School, Okoh-cho, Nankoku-city, Kochi 783-8505, Japan.
Brain Res. 2005 Jun 28;1048(1-2):131-7. doi: 10.1016/j.brainres.2005.04.065.
Previous studies have demonstrated that various types of stress increase type 1 corticotropin-releasing hormone (CRH) receptor (currently abbreviated to CRF1 receptor) mRNA in the hypothalamic paraventricular nucleus (PVN) of rats, but not mice. This study investigated whether different sensitivities of glucocorticoid-mediated negative feedback effects can explain this species difference in stress-induced PVN CRF1 receptor mRNA expression. First, the CRF1 receptor mRNA level in the PVN of CRH knockout (KO) mice during acute restraint stress was compared with that in wild-type (WT) mice. Consistent with previous findings, WT mice showed no induction of CRF1 receptor mRNA in the PVN following acute restraint, regardless of normal hypothalamic-pituitary-adrenocortical responses. In contrast, CRF1 receptor mRNA in the PVN of CRH KO mice was increased following 2 h of restraint. Since the response of tyrosine hydroxylase (TH) mRNA in the locus coeruleus (LC) to restraint was similar between CRH KO and WT mice, it is unlikely that enhanced noradrenergic input into the PVN was responsible for the CRF1 receptor mRNA induction in CRH KO mice. Second, to determine whether CRH KO per se or a low corticosterone response to stress is required to induce CRF1 receptor mRNA expression in the PVN in mice, the response of adrenalectomized WT mice was examined. Acute restraint increased the CRF1 receptor mRNA level in the PVN of adrenalectomized WT mice, similar to the case for CRH KO mice. TH mRNA in the LC showed similar increases in sham and adrenalectomized WT mice. These results indicate that PVN CRF1 receptor mRNA is much more sensitive to glucocorticoid-mediated negative feedback in mice than in rats, such that a normal increase in plasma corticosterone during stress can mask CRF1 receptor mRNA induction in the PVN of mice.
先前的研究表明，各种类型的应激会增加大鼠下丘脑室旁核（PVN）中1型促肾上腺皮质激素释放激素（CRH）受体（目前简称为CRF1受体）的mRNA水平，但对小鼠却没有这种作用。本研究调查了糖皮质激素介导的负反馈效应的不同敏感性是否可以解释这种应激诱导的PVN中CRF1受体mRNA表达的种属差异。首先，将急性束缚应激期间CRH基因敲除（KO）小鼠PVN中的CRF1受体mRNA水平与野生型（WT）小鼠进行比较。与先前的研究结果一致，无论下丘脑-垂体-肾上腺皮质反应是否正常，急性束缚后WT小鼠PVN中的CRF1受体mRNA均未出现诱导现象。相反，束缚2小时后，CRH KO小鼠PVN中的CRF1受体mRNA增加。由于蓝斑（LC）中酪氨酸羟化酶（TH）mRNA对束缚的反应在CRH KO小鼠和WT小鼠中相似，因此不太可能是PVN中去甲肾上腺素能输入增强导致了CRH KO小鼠中CRF1受体mRNA的诱导。其次，为了确定是CRH KO本身还是对应激的低皮质酮反应导致小鼠PVN中CRF1受体mRNA表达的诱导，研究了肾上腺切除的WT小鼠的反应。急性束缚增加了肾上腺切除的WT小鼠PVN中CRF1受体mRNA水平，与CRH KO小鼠的情况相似。LC中的TH mRNA在假手术和肾上腺切除的WT小鼠中显示出类似的增加。这些结果表明，PVN中CRF1受体mRNA对糖皮质激素介导的负反馈在小鼠中比在大鼠中更敏感，以至于应激期间血浆皮质酮的正常增加可以掩盖小鼠PVN中CRF1受体mRNA的诱导。
