Mechanisms of stress-Induced Persistent Hypertension PROJECT SUMMARY Prolonged and persistent stress is a known risk factor in the development of hypertension. Previous stud- ies have shown that in borderline hypertension, chronic stress-induced increases in arterial blood pressure last for a long period after termination of stress paradigms. However, the underlying mechanisms remain unknown. Chronic stress activates corticotropin-releasing hormone (CRH)-expressing neurons in the hypo- thalamus and central nucleus of the amygdala (CeA), which play a key role in regulating autonomic and cardiovascular functions during psychological stress, fear, and anxiety. The overall objective of our project is to determine the role of CeA-CRH neurons in the development of persistent hypertension and the mech- anisms involved. Our preliminary data showed that selectively inhibiting CeA-CRH neurons through a chemogenetic approach prevented chronic stress-induced hypertension in borderline hypertensive rats (BHRs) and that hyperactivity of CeA-CRH neurons was due to a reduction of K+ channel activity resulting from stress-induced increases in histone deacetylase (HDAC) activity. Our pilot study also showed that in- hibition of HDAC activity in the CeA in chronically stressed rats restored K+ expression and decreased fir- ing activity of CeA-CRH neurons. In this proposal, we will test the central hypothesis that hyperactivity of CeA-CRH neurons is responsible for stress-induced hypertension in BHRs and that a reduction in K+ channel activity caused by stress-induced upregulation of HDAC leads to hyperactivity of CeA-CRH neu- rons in stress-induced hypertension. Because the chronic unpredictable mild stress rat model closely re- sembles precipitation of depression by chronic and low-grade stressors in humans, this model will be used to test the hypothesis. We have 4 specific aims: We will attempt to determine the role of CeA-CRH neurons in the sustained hypertension in chronically stressed BHRs (aim 1), determine the role of CeA-CRH neu- rons in regulating blood pressure and sympathetic outflow in chronically stressed BHRs (aim 2), determine the role of K+ channels in the CeA in hyperactivity of CeA-CRH neurons and heightened sympathetic out- flow in chronically stressed BHRs (aim 3), and identify the epigenetic mechanisms involved in long-lasting downregulation of K+ channels in chronically stressed BHRs (aim 4). Our proposal is innovative because findings from our proposal are expected to provide novel information about the cellular and molecular mechanisms responsible for stress-induced persistent hypertension in borderline hypertension. This new information is significant because it may provide an important rationale for development of new strategies to treat neurogenic hypertension.
Hypertension remains a major clinical problem and therapeutic change. We plan to determine the role of CRH neurons in the amygdala in the development of stress-induced persistent hypertension. The proposed studies will provide an important rationale for the developing new treatment strategies to normalize elevated blood pressure in stress-induced persistent hypertension.
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|Zhou, Jing-Jing; Gao, Yonggang; Zhang, Xiangjian et al. (2018) Enhanced Hypothalamic NMDA Receptor Activity Contributes to Hyperactivity of HPA Axis in Chronic Stress in Male Rats. Endocrinology 159:1537-1546|