Elucidating the synaptic and cellular basis of cerebral hemodynamics

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Hemodynamic and metabolic imaging approaches are used to study cognitive and network function in the mammalian brain, yet the precise relationship between these macro- or meso-scale functional imaging signals and neuronal activity is not fully understood. In the brain, blood flow increases locally upon neuronal activation, however, the spatial, temporal, and quantitative relationship between hemodynamic signals and local brain activation remain unclear. I hypothesize that in order to ultimately understand how blood flow is regulated in complex vascular networks we need to investigate and discern neuronal-vascular interactions across the entire vascular tree. With the support of a NSERC discovery grant, I will establish a research program that aims to elucidate the synaptic and cellular basis of hemodynamic signals underlying functional imaging signals. Over the short term, we will focus on delineating the physiological mechanisms underlying cerebral blood flow regulation at different spatial scales. This work will be achieved by combining different imaging modalities to image sensory responses at both microscopic and mesoscopic resolution. Specifically, we will combine in vivo 2-photon imaging, with ultrafast functional ultrasound (fUS) in awake and behaving transgenic mice. By utilizing cellular and molecular manipulations we will delineate the physiological mechanisms underlying hemodynamic imaging signals. Over the short-term this work will be divided into 3 projects: 1) Determine the mechanisms regulating blood flow across different layers of the cerebral cortex in relation with local synaptic activation. 2) Establish quantitative relationships between neuronal and vascular responses during microcircuit plasticity. 3) Investigate cellular mechanisms underlying pericyte and smooth muscle cell Ca2+ signaling and their regulation of hemodynamic signals in vivo. This research program will discover basic physiological mechanisms underlying the regulation of blood flow in cerebral-vascular networks. By studying functional hyperemia at all scales, from mesoscopic fUS signals to the cellular mechanisms underlying them, we will begin to gain a complete picture of how complex cellular interactions mediate hemodynamic imaging signals, and thereby improve our understanding and interpretation of human brain imaging.