Foradori Chad D, Lund Trent D, Nagahara Alan H, Koenig James I, Handa Robert J
Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, CO 80523, USA.
Brain Res. 2007 Aug 20;1164:44-54. doi: 10.1016/j.brainres.2007.05.064. Epub 2007 Jun 12.
Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are pivotal mediators of the hormonal response to stressors and are found within neurons of the paraventricular nucleus of the hypothalamus (PVN) and several extrahypothalamic sites where expression is activity-dependent. Previous work has shown increased CRH immunoreactivity in extrahypothalamic sites after kainic-acid (KA)-induced seizures in male rats. This study examined the induction of CRH heterogeneous nuclear RNA (hnRNA), AVP hnRNA and c-fos as a measure of gene transcription and cell activation following kainic-acid (KA)-induced seizures. KA or saline was administered to intact male rats, ovariectomized (OVX) females and OVX females treated with 17beta-estradiol (E2). Animals were sacrificed 0, 15, 60 or 120 min following KA treatment. In the PVN, CRH hnRNA levels were increased by KA treatment at 15, 60, and 120 min. AVP hnRNA and c-fos mRNA in the PVN were also significantly elevated above controls at all time points. Elevations in CRH hnRNA were also identified in hippocampus, the lateral bed nucleus of the stria terminalis (BNST) and globus pallidus at 60 and 120 min following KA and in the piriform cortex, and central nucleus of the amygdala at 120 min after KA. CRH hnRNA levels at 120 min in the PVN, amygdala, cingulate cortex, hippocampus (CA1), piriform cortex, and BNST were lower in OVX+E2 females compared to females without E2. To determine if the increases in CRH hnRNA translated to increased CRH peptide, immunocytochemistry was performed. CRH immunoreactivity was increased in the amygdala, BNST, cingulate cortex, PVN and globus pallidus within 3 h after KA treatment and in the piriform cortex and hippocampus by 6 h after KA. These results suggest a time-dependent activation of the CRH system following activation of kainate receptors, which may result in long-term changes in the expression of extrahypothalamic CRH.
促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）是对应激源产生激素反应的关键介质，在下丘脑室旁核（PVN）的神经元以及几个下丘脑外位点中均有发现，这些位点的表达依赖于活性。先前的研究表明，在雄性大鼠中，经 kainic 酸（KA）诱导癫痫发作后，下丘脑外位点的 CRH 免疫反应性增加。本研究检测了 KA 诱导癫痫发作后，CRH 不均一核 RNA（hnRNA）、AVP hnRNA 和 c-fos 的诱导情况，以此作为基因转录和细胞激活的指标。将 KA 或生理盐水注射给完整雄性大鼠、去卵巢（OVX）雌性大鼠以及用 17β-雌二醇（E2）处理的 OVX 雌性大鼠。在 KA 处理后的 0、15、60 或 120 分钟处死动物。在 PVN 中，KA 处理后 15、60 和 120 分钟时，CRH hnRNA 水平升高。PVN 中的 AVP hnRNA 和 c-fos mRNA 在所有时间点也均显著高于对照组。在 KA 处理后 60 和 120 分钟时，海马、终纹床核外侧核（BNST）和苍白球中也发现 CRH hnRNA 升高，在 KA 处理后 120 分钟时，梨状皮质和杏仁核中央核中也发现 CRH hnRNA 升高。与未用 E2 的雌性大鼠相比，OVX+E2 雌性大鼠在 120 分钟时，PVN、杏仁核、扣带回皮质、海马（CA1）、梨状皮质和 BNST 中的 CRH hnRNA 水平较低。为了确定 CRH hnRNA 的增加是否转化为 CRH 肽的增加，进行了免疫细胞化学检测。KA 处理后 3 小时内，杏仁核、BNST、扣带回皮质、PVN 和苍白球中的 CRH 免疫反应性增加，KA 处理后 6 小时，梨状皮质和海马中的 CRH 免疫反应性增加。这些结果表明，在 kainate 受体激活后，CRH 系统存在时间依赖性激活，这可能导致下丘脑外 CRH 表达的长期变化。
