Multiple Genes Imbalances In The Paraventricular Nucleus Of Human Hypothalamus In Depression

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:(â…°)corticosteroid receptors and their chaperones,heat shock proteins(HSP)70 and 90,(â…±)sex hormone receptors,(â…²) CRH receptorsl(CRHR1)and 2(CRHR2),(â…³)cytokines interleukin 1beta(IL1B) and tumor necrosis factor alpha(TNFA),(â…´)neuropeptides and receptors,vasopressin (AVP),vasopressin receptor 1 a(AVPR1A)and oxytocin(OXT)and,(â…µ)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.