The brain requires constant delivery of oxygen (O2) and nutrients through the bloodstream to maintain healthy neuronal function. Indeed, local or global dips in O2, called hypoxia, can precipitate central nervous system damage and neurodegeneration. Critically, clinical manifestations of chronic hypoxia/ischemia primarily occur in deep brain structures such as the subcortical white matter and thalamus. Indeed, deep brain hypoxia/ischemia is a putative mechanism in ischemic small vessel disease, which is prevalent and debilitating, accounting for over ~40% of all dementia cases and is by far the leading cause of vascular dementia. Of the entire brain vascular landscape, over 90% of all vessels are exceptionally small capillaries, consisting of end-to-end endothelial cell tubes with complete coverage by embedded perivascular cells called pericytes. We have recently demonstrated that the capillaries provide a massive sensing surface area within the brain and can transduce environmental stimuli (such as neuronal activity) into reliable and robust increases in blood flow. We have also demonstrated that capillaries possess the molecular machinery required to transduce extracellular adenosine, a key hypoxia-induced signaling molecule, into vasodilation and increased blood flow. Additionally, capillaries are a critical locus for dysfunction in small vessel disease pathology. The main objectives of this proposal are to examine the role deep brain capillaries play in hypoxia-induced blood flow responses and to determine whether deep brain hypoxia-sensing is disrupted in an animal model of cerebral small vessel disease. Therefore, I hypothesize that capillary adenosine sensing mediates deep-brain blood flow responses during hypoxia. I further hypothesize that hypoxia sensing is diminished in cerebral small vessel disease, leading to vascular dysfunction and hypoxic damage in deep brain structures. I will test these hypotheses with two distinct aims. First, I will elucidate the role adenosine signaling and KATP channel activity play in hypoxia-induced deep brain blood flow responses. Second, I will determine whether cSVD pathology disrupts hypoxia-induced blood flow responses and capillary-mediated electrical signaling. This project will provide significant physiological and pathological insights into blood delivery mechanisms within the deep brain. This proposal is conceptually and technically innovative due to the capillary-centric examination of hypoxia-sensing and the use of sophisticated deep brain imaging in well-characterized models of cerebral small vessel disease.