Stress-induced glucocorticoid signaling remodels neurovascular coupling through impairment of cerebrovascular inwardly rectifying K⁺ channel function

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 20; pp. 7462 - 7467
• Main Authors: Longden, Thomas A., Dabertrand, Fabrice, Hill-Eubanks, David C., Hammack, Sayamwong E., Nelson, Mark T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.05.2014; National Acad Sciences
• Subjects: Amygdala; Amygdala - drug effects; Animals; Arterioles; Arterioles - drug effects; Astrocytes - metabolism; Behavioral neuroscience; Biological Sciences; Brain; Brain - drug effects; Brain - physiopathology; Brain diseases; Corticosterone; Corticosterone - chemistry; Current density; Genotype & phenotype; Glucocorticoids; Glucocorticoids - metabolism; Glucose - metabolism; Hormone Antagonists - chemistry; Limbic System - drug effects; Male; Mifepristone - chemistry; Neurons; Neurons - physiology; Oxygen - metabolism; Phenotype; Potassium Channels, Inwardly Rectifying - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction; Smooth muscle; Stress, Psychological; Time Factors; Vasodilation; Vasodilation - drug effects; limbic system; chronic stress; potassium channels; neurovascular unit
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1401811111

Studies of stress effects on the brain have traditionally focused on neurons, without considering the cerebral microcirculation. Here we report that stress impairs neurovascular coupling (NVC), the process that matches neuronal activity with increased local blood flow. A stressed phenotype was induced in male rats by administering a 7-d heterotypical stress paradigm. NVC was modeled by measuring parenchymal arteriole (PA) vasodilation in response to neuronal stimulation in amygdala brain slices. After stress, vasodilation of PAs to neuronal stimulation was greatly reduced, and dilation of isolated PAs to external K ⁺ was diminished, suggesting a defect in smooth muscle inwardly rectifying K ⁺ (K IR) channel function. Consistent with these observations, stress caused a reduction in PA K IR2.1 mRNA and smooth muscle K IR current density, and blocking K IR channels significantly inhibited NVC in control, but not in stressed, slices. Delivery of corticosterone for 7 d (without stressors) or RU486 (before stressors) mimicked and abrogated NVC impairment by stress, respectively. We conclude that stress causes a glucocorticoid-mediated decrease in functional K IR channels in amygdala PA myocytes. This renders arterioles less responsive to K ⁺ released from astrocytic endfeet during NVC, leading to impairment of this process. Because the fidelity of NVC is essential for neuronal health, the impairment characterized here may contribute to the pathophysiology of brain disorders with a stress component.