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Bridging the gap between cellular imaging and fMRI BOLD imaging

Final Report Summary - IMAGING-INTHE-MAGNET (Bridging the gap between cellular imaging and fMRI BOLD imaging)

The brain is the most metabolically active tissue in the body; it consists of 2% of the human body’s weight yet uses 20 % of the body’s energy. Initially, it was assumed that during brain activation, the increase in blood flow, named functional hyperemia, reflected metabolic consumption and thus the energy demand of activated neurons and glial cells. It is now established that functional hyperemia regulation mostly depends on neurotransmitter signalling, which triggers a series of steps involving neurons, glial and vascular mural cells. A major importance of functional hyperemia, in addition to its role in supplying energy to the brain and clearing metabolites, is that it is used as a proxy to measure brain activity. In particular, the blood-oxygen-level-dependent (BOLD) signal, which is commonly used for functional magnetic resonance imaging (fMRI) of brain activity, has provided an efficient and widespread tool to investigate normal and pathological brain function in humans. Yet, BOLD signals detect changes in the concentration of deoxyhemoglobin, and as such depends in a complex manner on functional hyperemia, oxygen consumption and blood volume. Consequently, the extent to which these signals report local neuronal activation at the cellular level remains unknown, raising uncertainties regarding signal interpretation for clinical application. Using the rodent olfactory bulb as a neurovascular model, two-photon imaging, functional ultrasound imaging and BOLD fMRI,
We have investigated several questions with micrometric spatial resolution: How does functional hyperemia depend on neurons, astrocytes and contractile cells? How does the brain’s oxygen partial pressure match neuronal activation and blood flow? What is the spatial and temporal overlap between mesoscopic fMRI BOLD or functional ultrasound signals and functional hyperemia at the local capillary level?
We have found that i) the dynamics of astrocyte processes are fast enough to participate to neurovascular coupling (Otsu et al. Nat. Neurosci. 2005) and ii) Functional hyperemia triggers a signal that back-propagates triggering dilation of specific capillary compartments and arterioles (Rungta et all. Neuron, 2018).
We have developed a new approach allowing measurements PO2 with a microscopic resolution in the brain of awake unstressed mice (Lyons et al. eLife 2016). We have also found that measurements per se affect blood flow and PO2 in the brain (Roche et al. eLife 2019).
We have developed a preparation and the tools allowing measurements of blood flow with two-photon microscopy, functional ultrasound and BOLD fMRI in the same animal.We have shown that in the olfactory bulb, microscopic and mesoscopic vascular signals are linearly correlated to neuronal calcium signalling (Boido et al. Nat. Commun. 2019).