Adequate perfusion is essential for normal brain function and impaired regulation of cerebral blood flow (CBF) may contribute to neurological dysfunction and disease. Despite recent progress, our knowledge of mechanisms that regulate CBF remains inadequate. Two of the most powerful stimuli that affect CBF are hypercapnia and increased cellular activity (cellular metabolism and synaptic activity). Both of these stimuli increase local concentrations of hydrogen ion (reduce extracellular pH). The overall goal of this application is to examine the role of acid-sensing ion channels (ASICs) in control of CBF. We found recently that ASICs are required for acid-evoked effects on synaptic plasticity. Moreover, the ASIC1a subtype functions as a chemosensor in neurons mediating hypercapnia- and acid-evoked behaviors. These findings led to preliminary experiments testing whether ASICs also play a role in regulation of CBF. Although effects of hypercapnia and acidosis have been known for decades, mechanisms that initiate vascular responses to these stimuli remain undefined. Based on this background, we propose two Aims.
Aim 1 will examine the hypothesis that ASICs mediate vascular responses to hypercapnia. We will examine vascular effects of hypercapnia and acidosis following manipulation of ASICs using genetic and pharmacological approaches. To define the importance of neuronal ASIC, we will take advantage of mice lacking or overexpressing ASIC1a specifically in neurons. We will also use ASIC inhibitors to pharmacologically probe ASIC function.
Aim 2 will use similar approaches to examine the hypothesis that neuronal ASICs contribute to vascular responses in models of neurovascular coupling. In pilot studies, we found that disrupting ASIC1a nearly eliminated hypercapnia-induced vasodilation but also significantly attenuated vasodilator responses in a model of neurovascular coupling. Together these studies will unambiguously determine the importance and site of ASIC action in hypercapnia- and proton-dependent regulation of cerebrovascular responses. The studies may provide new and unprecedented insight into the complex interaction between brain and its vascular supply. Such insight may ultimately lead to improved therapeutic approaches for cerebrovascular disease and brain injury. This project was conceived and will be carried out by an innovative collaboration between investigators with diverse expertise in CBF, neurovascular coupling, pH regulation, and ASICs.
Optimal regulation of cerebral blood flow is critical for brain function. Abnormalities in the control of cerebral blood flow lead to brain dysfunction and even cell death. The goal of these studies is to further elucidate mechanisms that regulate brain blood flow but examining the role of acid-sensing ion channels in the control of cerebral blood flow. These studies will provide new insight into the complex interaction between brain and its vascular supply. Such knowledge may ultimately lead to improved therapeutic approaches for cerebrovascular disease and brain injury.
|De Silva, T Michael; Ketsawatsomkron, Pimonrat; Pelham, Christopher et al. (2015) Genetic interference with peroxisome proliferator-activated receptor ? in smooth muscle enhances myogenic tone in the cerebrovasculature via A Rho kinase-dependent mechanism. Hypertension 65:345-51|
|Taugher, Rebecca J; Lu, Yuan; Wang, Yimo et al. (2014) The bed nucleus of the stria terminalis is critical for anxiety-related behavior evoked by CO2 and acidosis. J Neurosci 34:10247-55|
|Chrissobolis, Sophocles; Drummond, Grant R; Faraci, Frank M et al. (2014) Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens 32:1815-21|
|Johnson, Casey P; Heo, Hye-Young; Thedens, Daniel R et al. (2014) Rapid acquisition strategy for functional T1? mapping of the brain. Magn Reson Imaging 32:1067-77|
|Magnotta, Vincent A; Johnson, Casey P; Follmer, Robin et al. (2014) Functional t1? imaging in panic disorder. Biol Psychiatry 75:884-91|
|Joutel, Anne; Faraci, Frank M (2014) Cerebral small vessel disease: insights and opportunities from mouse models of collagen IV-related small vessel disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 45:1215-21|
|De Silva, T Michael; Modrick, Mary L; Ketsawatsomkron, Pimonrat et al. (2014) Role of peroxisome proliferator-activated receptor-? in vascular muscle in the cerebral circulation. Hypertension 64:1088-93|
|Heo, Hye-Young; Wemmie, John; Thedens, Daniel et al. (2014) Evaluation of activity-dependent functional pH and T1? response in the visual cortex. Neuroimage 95:336-43|
|Kreple, Collin J; Lu, Yuan; Taugher, Rebecca J et al. (2014) Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat Neurosci 17:1083-91|
|Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M et al. (2014) Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis. FASEB J 28:1735-44|
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