Molecular Psychiatry：抑郁症病人脑内多基因平衡紊乱的证据
中国科学技术大学生命科学学院周江宁教授与荷兰的科学家合作，利用荷兰人脑库提供的人脑组织标本，首次应用激光显微切割技术研究了抑郁症病人脑中负责应激反应和情绪调节的一个中枢（下丘脑）的改变。下丘脑只有成人的拇指指头大小，但非常复杂，含有多种微小的，由不同功能神经细胞群组成的核团。因此，需要利用新型的激光分离技术将其中的一个特定核团既室旁核，分离出来进行特异性的研究（周江宁教授课题组的王姗姗同学完成了具体研究工作）。
下丘脑室旁核中含有一群细胞，既促肾上腺激素释放因子（CRF）细胞，它们扮演着人体应激反应的中枢驱动的角色，在抑郁症病人脑中异常活跃。该研究利用激光显微分离室旁核区域并结合荧光定量分析技术，对抑郁症和正常人室旁核中16个参与调节CRF活性的相关基因表达进行了分析。发现在抑郁症下丘脑室旁核中，5个基因的上调或下调与抑郁症发病相关。这些基因表达的改变，不仅能够解释为何在抑郁症中CRF细胞活性增高，而且为寻找治疗抑郁症的药物提供了新的靶点。
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Molecular Psychiatry advance online publication 22 April 2008; doi: 10.1038/mp.2008.38
Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances
S-S Wang1,2, W Kamphuis1, I Huitinga1, J-N Zhou2 and D F Swaab1
- 1Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
- 2Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology and Biophysics, Life Science School, University of Science and Technology of China, Hefei, Anhui, PR China
Abstract
Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-
and tumor necrosis factor-
, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. 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 microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF 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.
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