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A Novel Non‐Linear Approach to Characterizing Astrocytic Neurovascular Coupling with Optogenetics and Computational Modeling

The role of astrocytes in neurovascular coupling remains hotly contested with various proposed mechanisms of hemodynamic response. Past findings have proven calcium activity to be the essential component in all astrocytic pathways of vascular control. However, these findings have proven contradictory over the last two decades, suggesting that an additive approach may not be appropriate for the quantification and characterization of astrocytic neurovascular coupling. We hypothesize that these astrocyte‐governed biochemical pathways have an unequal contribution and that they enact hemodynamic change in a dynamic, non‐linear fashion. Using a tetracycline‐based transgenic mice model, expressing ChR2‐EYFP solely in astrocytes, we optogenetically stimulated the production of a calcium wave in mice cortical astrocytes and evaluated hemodynamic change with a Laser Doppler Flowmetry (LDF) modality. Under these conditions, a sustained increase in localized perfusion of around 20% was found within stimulated areas. Subsequent pharmacological inhibition of phospholipase (PLA2) governed pathways facilitated the characterization of PLA2isoforms within cortical astrocytes. Furthermore, we created a computational biophysical model of hemodynamic response aiming to reproduce the experimental data generated from this study and previous ones. This data better elucidates the role of astrocytes in regional resource delivery, suggesting a new perspective in the diagnosis, treatment, and prevention of neurodegenerative diseases with vascular presentations such as Alzheimer’s Disease. We believe our findings provide a new approach by which future studies may revisit the use of pharmacology to characterize the neurovascular coupling phenomenon.