【作者】 王姗姗；

【导师】 周江宁；

【作者基本信息】 中国科学技术大学 ， 神经生物学， 2008， 博士

【摘要】 下丘脑室旁核(PVN)中的促肾上腺皮质激素释放激素(CRH)神经元活性上调是抑郁症的主要神经生物学特征。因此,CRH在抑郁症的发病机制中到重要的作用。PVN中CRH神经元受以下诸多因素激动或抑制性调节:(ⅰ)糖激素受体GR和盐皮质激素受体MR及其伴侣分子热休克蛋白(HSP)70和HSP90;(ⅱ)雌激素受体ESR和雄激素受体AR;(ⅲ)CRH受体CRHR1和CRHR2;(ⅳ)细胞因子白介素1β(IL1B)和肿瘤坏死因子α(TNFA):(ⅴ)血管加压素(AVP)及其受体AVPR1A、催产素(OXT);(ⅵ)转录因子CREB。我们假设抑郁症患者下丘脑促进下丘脑-垂体-肾上腺(HPA)轴的基因转录水平上调,而对HPA轴起到抑制作用的基因转录水平下调。我们首次利用激光显微分离技术结合实时定量PCR,在抑郁症(N=7)和正常对照(N=7)人尸检的下丘脑,定量分析这些与CRH活性调控有关的基因转录水平的改变。分析结果发现,抑郁症组下丘脑PVN中CRH转录水平显著增高,伴随着多受体基因转录的改变。其中,这些促进CRH基因表达或者可激活CRH神经元活性的基因,如CRHR1,ESR1,MR,AVPR1A的转录水平比正常组高,而抑制CRH基因表达的AR低于正常组。根据我们的研究结果,提出抑郁症中下丘脑室旁核多受体平衡紊乱假说,可能与抑郁症中HPA轴活性上调有关,对抑郁症发病机制研究提出了新的研究思路,并且为临床治疗提供了新的治疗靶点。更多还原

【Abstract】 Hyperactivity of corticotropin-releasing hormone(CRH)neurons in the paraventricular nucleus(PVN)of the hypothalamus is a prominent feature in depression and may play a central role in the etiology of this disease.The activity of the CRH neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRH expression,including:(ⅰ)corticosteroid receptors and their chaperones,heat shock proteins(HSP)70 and 90,(ⅱ)sex hormone receptors,(ⅲ) CRH receptorsl(CRHR1)and 2(CRHR2),(ⅳ)cytokines interleukin 1beta(IL1B) and tumor necrosis factor alpha(TNFA),(ⅴ)neuropeptides and receptors,vasopressin (AVP),vasopressin receptor 1 a(AVPR1A)and oxytocin(OXT)and,(ⅵ)transcription factor CREB.We hypothesized that,in depression,the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal(HPA)-axis are upregulated whereas the transcript levels of the genes involved in the inhibition of the HPA-axis are downregulated.We performed laser micro-dissection and real time PCR in the PVN and as a control in the supraoptic nucleus(SON).Snap frozen postmortem hypothalami of 7 depressed and 7 matched controls were used.We found significantly increased CRH mRNA levels in the PVN of the depressed patients.This was accompanied by a significantly increased expression of 4 genes that are involved in the activation of CRH neurons,i.e.CR.HR1-,estrogen receptor alpha(ESR1), AVPR1A and mineralocorticoid receptor(MR),while the expression of the androgen receptor(AR)mRNA involved in the inhibition of CRH neurons was decreased significantly.These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA-axis in depression.This study indicates new research targets for future work,and may also offer new therapeutic strategies for depressed patients.更多还原