University of Illinois at Chicago, Department of Psychiatry, Chicago, IL 60612, USA.
University of Illinois at Chicago, Department of Psychiatry, Chicago, IL 60612, USA.
Psychoneuroendocrinology. 2019 Aug;106:233-243. doi: 10.1016/j.psyneuen.2019.04.015. Epub 2019 Apr 15.
Overactivity of hypothalamic-pituitary-adrenal (HPA) axis function has been implicated in depression and suicidal behavior. This is based on the observation of an abnormal dexamethasone (DEX) and DEX-adrenocorticotropic hormone (ACTH) test in patients with depression and suicidal behavior. Recently, some studies have also found abnormalities of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), corticotropin releasing factor (CRF), CRF receptors (CRF-R) and CRF binding protein (CRF-BP) in depressed and suicidal patients. Some investigators have also observed increased levels of CRF in the cerebrospinal fluid (CSF) and altered levels of MR, GR and CRF in the postmortem brain of depressed and suicidal subjects. We have earlier reported decreased protein and mRNA expression of GR and GILZ, a chaperone protein, in the postmortem brain of teenage suicide subjects. We have further studied CRF and its receptors in different areas of the postmortem brain of suicide subjects, i.e., the prefrontal cortex (PFC), hippocampus (HIPPO), subiculum and amygdala (AMY) from teenage suicide subjects. The CRF and its receptors were determined in the PFC (Brodmann area 9), HIPPO, subiculum and different amygdaloid nuclei from 24 normal control subjects and 24 teenage suicide subjects. Protein expression of CRF, its receptors and CRF-BP was determined by immunolabeling using the Western blot technique and mRNA expression was determined by real-time PCR (qPCR) technique. We found that the mRNA levels of CRF were significantly increased in the PFC, in the central amygdaloid nucleus (CeAMY) and in the subiculum. mRNA levels of CRF-R1 and CRF-BP were significantly decreased in the PFC. We did not find any changes in the HIPPO of any of the CRF components we studied. When we compared the protein expression of CRF components we found that CRF was significantly increased and CRF-R1, CRF-R2 and CRF-BP significantly decreased in the PFC. On the other hand, there were no changes in the protein expression of CRF components in the HIPPO. Our results in the postmortem brain suggest that, as found by clinical studies in the CSF, there are significant alterations of CRF and its receptors in the postmortem brain of teenage suicide subjects. These alterations of CRF and its components were region-specific, as changes were not generally observed in the HIPPO.
下丘脑-垂体-肾上腺（HPA）轴功能的过度活跃与抑郁和自杀行为有关。这是基于对抑郁和自杀行为患者中异常地塞米松（DEX）和 DEX-促肾上腺皮质激素（ACTH）测试的观察。最近，一些研究还发现抑郁和自杀患者的糖皮质激素受体（GR）、盐皮质激素受体（MR）、促肾上腺皮质释放因子（CRF）、CRF 受体（CRF-R）和 CRF 结合蛋白（CRF-BP）存在异常。一些研究人员还观察到脑脊液（CSF）中 CRF 水平升高，以及抑郁和自杀受试者死后大脑中 MR、GR 和 CRF 水平改变。我们之前报道过，青少年自杀者死后大脑中 GR 和作为伴侣蛋白的 GILZ 的蛋白和 mRNA 表达减少。我们进一步研究了自杀者死后大脑不同区域的 CRF 及其受体，即来自青少年自杀者的前额叶皮层（PFC）、海马体（HIPPO）、下托和杏仁核（AMY）。CRF 及其受体在 24 名正常对照者和 24 名青少年自杀者的 PFC（Brodmann 区域 9）、HIPPO、下托和不同的杏仁核核中进行了测定。使用 Western blot 技术通过免疫标记法测定 CRF、其受体和 CRF-BP 的蛋白表达，并通过实时 PCR（qPCR）技术测定 mRNA 表达。我们发现，PFC、中央杏仁核核（CeAMY）和下托中的 CRF mRNA 水平显著增加。PFC 中的 CRF-R1 和 CRF-BP mRNA 水平显著降低。我们没有发现我们研究的任何 CRF 成分在 HIPPO 中的任何变化。当我们比较 CRF 成分的蛋白表达时，我们发现 PFC 中的 CRF 显著增加，而 CRF-R1、CRF-R2 和 CRF-BP 显著降低。另一方面，HIPPO 中 CRF 成分的蛋白表达没有变化。我们在尸检大脑中的结果表明，正如临床研究在 CSF 中发现的那样，青少年自杀者尸检大脑中存在 CRF 及其受体的显著改变。这些 CRF 及其成分的改变是特定区域的，因为一般不会在 HIPPO 中观察到变化。
