下丘脑室旁核CRH神经元调控高血压的神经机制研究

下丘脑室旁核(PVN)前交感神经元过度兴奋是高血压时交感活动增强、血压增高的重要机制。PVN促肾上腺皮质激素释放激素(PVN-CRH)神经元介导机体应激反应、参与心血管活动调控，在高血压时过度激活。然而，有关高血压时两类神经元之间是否具有功能联系、PVN前交感神经元兴奋性增高的来源和PVN-CRH神经元过度激活的机制仍知之甚少。我们前期研究发现，下丘脑PVN前交感神经元分布CRH受体(CRHR)，且CRHR1在自发性高血压大鼠(SHR)表达增多；抑制PVN中CRHR1可降低SHR交感传出活动和血压。我们推测，PVN-CRH神经元通过释放CRH，作用于CRHR1使PVN前交感神经元兴奋性增高，交感传出活动增加、血压升高。本课题拟从整体、细胞和分子等水平探讨下丘脑PVN-CRH神经元在高血压中的作用和神经调控机制。研究结果将为高血压的防治提供新策略或靶点，具有重要的理论意义和潜在的应用价值。

The PVN presympathetic neurons play an important role in the development of hypertension through augmenting sympathetic activity. However, the exact sources of excitatory input to PVN presympathetic neurons in hypertension are unclear. The corticotrophin-releasing hormone (CRH) neurons, which typically mediate stress response, are over-activated and may contribute to hyperactivity of PVN presympathetic neurons in hypertension. However, little is known about the interaction between CRH neurons and presympathetic neurons in the PVN in hypertension. The mechanism of PVN-CRH neurons hyperactivity remains unclear, as well. Our preliminary studies showed that CRH receptors were distributed on PVN presympathetic neurons and that the protein level of CRH receptor-1 was higher in spontaneously hypertensive rats (SHR) than in normotensive rats. Furthermore, blocking CRH receptor-1 in the PVN decreased sympathetic nerve discharges and blood pressure in SHR. We thus hypothesize that increased excitability of CRH neurons, by releasing CRH and binding to CRH receptor-1 in presympathetic neurons in the PVN, is critically involved in maintaining hyperactivity of PVN presympathetic neurons and heightened sympathetic outflow in hypertension. In this proposal, we will investigate the contribution of CRH neurons in the PVN to the development of hypertension at the system, cellular, and molecular levels. The findings from the proposed studies will provide new strategies or targets to the prevention and treatment for hypertension, which have important theoretical and practical significance.