Activation of Corticotropin‐Releasing Hormone Neurons in the Central Nucleus of Amygdala is required for Chronic Stress‐Induced Hypertension

Abstract

Background Chronic stress is a well-known risk factor for the etiology of hypertension. However, the underlying neural mechanisms remain largely unknown. Corticotropin-releasing hormone (CRH) neuroendocrine cells in central nucleus of the amygdala (CeA) are critical in mediating autonomic response to chronic stress. Therefore, we determined the role of CeA-CRH neurons in hypertension induced by chronic stress. Methods Broadline hypertensive rats (BHRs) were subjected to chronic unpredictable stress (CUS). Identified CeA-CRH neuron firing activity and M-currents were recorded by whole-cell patch-clamp technique in brain slice preparation. A CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. Kv7 channel protein and mRNA level were determined by western-blot and quantitative RT-PCR methods, respectively. Results CUS treatment induced a sustained elevation of blood pressure in BHRs and a significant increase in c-Fos expression CeA-CRH neurons. Identified CeA-CRH neurons displayed significantly higher spontaneous firing activities in BHRs subjected to CUS than in unstressed BHRs. Specifically suppressing CeA-CRH neurons activity by using CRH-Cre-directed chemogenetic approach restrained CUS-induced sustained hypertension in BHRs. Both mRNA and protein levels of Kv7.2 and Kv7.3 channels were decreased in CeA of BHRs subjected to CUS. M-currents recorded from CeA-CRH neurons were significantly decreased in CUS BHRs compared with unstressed BHRs. Blocking Kv7 channel with its specific antagonist increased excitability of CeA-CRH neurons in unstressed BHRs whereas did not alter their excitability in BHRs subjected to CUS. Conclusions These data suggest that CeA-CRH neurons are required for the development of chronic stress-induced hypertension. The hyperactivity of CeA-CRH neurons is due to impaired Kv7 channel activity induced by chronic stress. These findings revealed a novel mechanism involved in chronic stress-induced hypertension.