PROJECT SUMMARY/ABSTRACT – OVERALL We seek to understand the nature of the pial neurovascular circuit, whose dynamics is characterized by ultralow frequency oscillations near 0.1 Hz that parcellate into separate coherent regions across cortex. We will use this knowledge to form a mathematical relation between the hemodynamic patterns observed in optical and functional magnetic resonance imaging experiments and the underlying brain state. Our proposed studies propose to leverage our experimental expertise in in vivo optical microscopy in mouse and fMRI in mouse and human. These primary modalities for data acquisition are combined with behavioral training, electrophysiology, and data analysis. Our experimental effort is parallel by two theoretical efforts. One mixed analytical/computational effort is on coupled oscillator dynamics to formulate models, at varying levels of complexity, of the pial neurovascular circuit. A second solely computational effort concerns the modulation of the transport of oxygen, by regional oscillations of the pial neurovascular circuit. The pial neurovascular circuit is composed of a two-dimensional network of pial arterioles that undergo rhythmic oscillations in the ~ 0.1 Hz vasomotor band. Each element in this circuit - a segment of arteriole whose diameter is modulated by the constriction/dilation of smooth muscle, contains an intrinsic rhythm generator, much like intrinsic bursting neurons in central pattern generators. The pial arterioles integrate neuronal activity from neighboring arterioles, underlying neurons, subcortical neurons, and neuromodulatory centers to produce dynamic patterns of coherent oscillations in arteriolar diameter across the cortical mantle. These patterns contain regions that oscillate at slightly different frequencies, i.e., they parcellate into separate regions. The fascinating issue is that the parcellation only partially reflects input from the directly underlying neuronal input. We seek to understand, model, and exploit this parcellation. The PIs have collaborated on issues in neuroscience and neurovascular science for many years. This proposal is a result of their discoveries and converging interest in a structured collaborative effort. Project 1 will formulate an understanding of fundamental physiology of the pial neurovascular circuit. This includes determining if brain arterioles truly act as interacting non-linear oscillators, i.e., that they entrain and phase-lock rather than passively filter. Projects 1, 2, and 4 will explore experimentally and theoretically how four competitive interactions, viz, input from neighboring arterioles, (ii) input from underlying neurons, (iii) input from subcortical areas involved in homeostasis; and (iv) input from brain neuromodulatory centers, lead to the observed patterns of pial neurovascular activity. Projects 2 and 4 will explore and model the regulation of oxygen in subsurface vessels, while Project 3 will expand the resolution of MR imagi...