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 7

NKCC1 inhibition reduces sympathetic vasomotor tone and enhances sympathoinhibitory responses to GABAA receptor activation in the CeA in chronic stress-induced hypertension.

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NKCC1 inhibition reduces sympathetic vasomotor tone and enhances sympath...
(A and B) Raw recording traces show the effect of bumetanide (BUM, 200 μmol, 10 μL, icv.) and bilateral injection of muscimol (Mus, 1 nmol, 100 nl, CeA injection) on the ABP, HR, RSNA and Int. RSNA in CUMS BHRs. (C–E) Summary data show changes of MAP (C), HR (D) and Int. RSNA (E) in response to muscimol microinjection into the CeA following icv. administration of BUM or vehicle (n = 6 rats in each group). (F) Representative images show the microinjection site in the CeA. (G) Schematic drawings show the microinjection sites of muscimol in the CeA pre-treated with vehicle (○) and those microinjection sites pre-treated with BUM (∆) in CUMS BHRs. icv: intracerebroventricular. CeA, central nucleus of amygdala. BLA, basolateral nucleus of amygdala. Veh: vehicle. OX, optic chiasm. Data are expressed as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA followed by Tukey’s post hoc test.