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Quantifying the structure-function of the neurovascular interface: from micro-circuits to large-scale functional organization

Periodic Reporting for period 4 - MultiScaleNeurovasc (Quantifying the structure-function of the neurovascular interface: from micro-circuits to large-scale functional organization)

Reporting period: 2019-12-01 to 2021-05-31

The brain utilized is the most energy an oxygen demanding organ in our body; despite representing about 2% of the total body mass, it consumes about 20% of the oxygen an energy. Such a high demand makes oxygen and metabolites precious resources that are distributed to active areas of the brain on a need-basis; a process called functional hyperimia.To facilitate this process, neuronal activity has to be translated to a local response in the vasculature to locally increase blood flow and thus delivery of oxygen and metabolites. In this process, we set to build the tools required to decipher this biological transform function (termed neurovascular coupling). It became clear that novel tools were required to attain our overarching goal as the common practice was to study this process using imaging approaches that provided obtained from a single imaging plane; even if we assumed only a spatial interaction of the order of 100micros, only 25% of the relevant information could have been obtained. This forced us to devote a significant effort towards developing a volumetric imaging approach and related image analysis tools; both directions resulted in technological development that enable now my group to acquire unique data consisting on neuronal and vascular activity of significant volumes of the mouse brain. We have made both the imaging and analysis tools openly available to the scientific community and seek also to translate part of our technology to a medical application. The technologies established this project have also allowed my laboratory to make contribution to the study of brain metastasis and stroke, all related to the structure and function of the brain vasculature.

With these novel tools at hand and much enthusiasm, we are continuing our quest to decipher the biological transfer function between neurons and blood vessels.
Biology does not "happen" in two-dimensions; on the contrary, it is withing complex three-dimensional interactions where it takes place. We have largely devoted efforts to tackle the unmet need to image neuronal and vascular activity in the living mouse brain in a volumetric fashion allowing us to generate, for the first time, the type of data that will help us to decipher the interaction between these key players in brain function. Given the complexity of these data, we have also devoted a significant effort to develop novel image analysis tools, based on machine learning, to extract the relevant information from this novel data.
As part of the work in this project, we have recently discovered that, despite working together, the vasculature around neuronal ensembles across different mouse brain regions that convey sensory information from the outside world to the brain, does not line up with these neuronal units. It seems like the solution to this apparent conundrum lies in the fine details of the neuronal-vascular microcircuity (i.e. understanding how single neuronal processes signal to the nearby vasculature). We are currently working to decipher this complex structural organization while mapping also the distribution of the cellular signaling machinery. We expect that once completed, this mapping will represent one of the most significant contributions of this project as we will have quantitatively defined a novel neuroscience concept: the neuro-glio-vascular synapse.
Optical setup with new imaging tools we develop to measure neural and vascular dynamics