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-β and tumor necrosis factor-α, (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-α, 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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Acknowledgements
We are indebted to the Netherlands Brain Bank at the Netherlands Institute for Neuroscience for providing us with the brain material and patient information. We thank Dr Michel A Hofman and Dr Aimin Bao for their statistical assistance, Dr Gerben Meynen for the psychiatric evaluations, Dimitra Kontostavlaki for providing us with the primers and Dr Elly Hol, Nathalie Koning, Dr Yinhui Wu, Tian Zhou, Bart Fisser, Rawien A Balesar, Arja A Sluiter, Unga A Unmehopa, Joop Van Heerikhuize and Paula van Hulten van Run for their technical advice. This investigation was supported by the projects of the Royal Netherlands Academy of Arts and Sciences (06CDP026) and the Natural Science Foundation of China (30530310).
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Wang, SS., Kamphuis, W., Huitinga, I. et al. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol Psychiatry 13, 786–799 (2008). https://doi.org/10.1038/mp.2008.38
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DOI: https://doi.org/10.1038/mp.2008.38
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