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.
|Johnson, Casey P; Christensen, Gary E; Fiedorowicz, Jess G et al. (2018) Alterations of the cerebellum and basal ganglia in bipolar disorder mood states detected by quantitative T1? mapping. Bipolar Disord 20:381-390|
|Shaffer Jr, Joseph J; Johnson, Casey P; Fiedorowicz, Jess G et al. (2018) Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. Brain Imaging Behav 12:837-847|
|Müller Ewald, Victória A; De Corte, Benjamin J; Gupta, Subhash C et al. (2018) Attenuation of cocaine seeking in rats via enhancement of infralimbic cortical activity using stable step-function opsins. Psychopharmacology (Berl) :|
|Faraci, Frank M (2018) Watching Small Vessel Disease Grow. Circ Res 122:810-812|
|De Silva, T Michael; Li, Ying; Kinzenbaw, Dale A et al. (2018) Endothelial PPAR? (Peroxisome Proliferator-Activated Receptor-?) Is Essential for Preventing Endothelial Dysfunction With Aging. Hypertension 72:227-234|
|De Silva, T Michael; Modrick, Mary L; Dabertrand, Fabrice et al. (2018) Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background. Hypertension 71:921-927|
|Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471|
|De Silva, T Michael; Hu, Chunyan; Kinzenbaw, Dale A et al. (2017) Genetic Interference With Endothelial PPAR-? (Peroxisome Proliferator-Activated Receptor-?) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70:559-565|
|Taugher, R J; Lu, Y; Fan, R et al. (2017) ASIC1A in neurons is critical for fear-related behaviors. Genes Brain Behav 16:745-755|
|Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia et al. (2017) Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries. Hypertension 69:60-70|
Showing the most recent 10 out of 36 publications