Chloride homeostasis dysfunction drives hyperactivation of corticotropin-releasing factor-expressing neurons in the amygdala in stress-induced hypertension
Hongyu Ma, Ying Zhang, Xinqi Guo, Qiyue Zhao, Peiyun Yang, Yan Liu, Yue Guan, Yan Wei, Huijie Ma
Hongyu Ma, Ying Zhang, Xinqi Guo, Qiyue Zhao, Peiyun Yang, Yan Liu, Yue Guan, Yan Wei, Huijie Ma
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Research Article Cell biology Neuroscience

Chloride homeostasis dysfunction drives hyperactivation of corticotropin-releasing factor-expressing neurons in the amygdala in stress-induced hypertension

Abstract

Stress promotes the progression from borderline hypertension to sustained hypertension, but the mechanism remains unclear. We investigated the role of corticotropin-releasing factor (CRF)-expressing neurons in the central nucleus of amygdala (CeA) on arterial blood pressure (ABP) and sympathetic activity of borderline hypertensive rats (BHRs) subjected to chronic unpredictable mild stress (CUMS). CUMS induced sustained hypertension, and led to increased delta-FosB expression as well as enhanced spontaneous and evoked firing of CeA CRF-expressing neurons in BHRs. Furthermore, optogenetic activation of CeA CRF-expressing neurons significantly increased the sympathetic outflow and ABP in BHRs. Impaired GABAergic inhibition, a depolarizing shift of GABA reversal potential (EGABA), disrupted chloride homeostasis and increased NKCC1 expression were observed in CeA CRF-expressing neurons in BHRs subjected to CUMS. NKCC1 inhibition with bumetanide restored GABAergic inhibition and chloride homeostasis, normalized neuronal excitability, leading to reduced sympathetic vasomotor tone in CUMS BHRs. These results indicate that NKCC1-mediated disruption of chloride homeostasis in CeA CRF-expressing neurons contributes to elevated sympathetic activity and hypertension under chronic stress. These findings enhance our understanding of the neuronal and molecular mechanisms underlying stress-induced hypertension and reveal potential targets for its prevention and treatment.

Authors

Hongyu Ma, Ying Zhang, Xinqi Guo, Qiyue Zhao, Peiyun Yang, Yan Liu, Yue Guan, Yan Wei, Huijie Ma

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Figure 5

CUMS results in the up-regulation of NKCC1 without affecting KCC2 in the CeA of BHRs.

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CUMS results in the up-regulation of NKCC1 without affecting KCC2 in the...
(A–C) Representative immunoblots and quantification of membrane NKCC1 protein in the CeA (A), frontal cortex (B) and RVLM (C) of WKY rats, CUMS WKY rats, BHRs and CUMS BHRs (n = 6 rats in each group). (D–F) Representative immunoblots and quantification of membrane KCC2 protein in the CeA (D), frontal cortex (E) and RVLM (F) of WKY rats, CUMS WKY rats, BHRs and CUMS BHRs (n = 6 rats in each group). Data are expressed as means ± SEM. **P < 0.01. One-way ANOVA followed by Tukey’s post hoc test. (G) Representative immunofluorescent images show CRF-positive neurons (green), NKCC1-positive neurons (red), and NKCC1 and CRF double-labeled neurons in the CeA of BHR and CUMS BHR (n = 5 rats in each group). (H and I) The percentage of CRF (H) or NKCC1 (I) positive neurons in the CeA of BHR and CUMS BHR. (J) The percentage of CRF and NKCC1 double positive neurons in the CeA of BHR and CUMS BHR. CeA, central nucleus of amygdala. RVLM, rostral ventrolateral medulla. Data are expressed as means ± SEM. ***P < 0.001. Two-tailed Student’s t-test.