This proposal aims to demonstrate that structural changes in brain capillaries are central to the metabolic and neurophysiological issues seen in Prader-Willi Syndrome (PWS). Dr. Schneeberger Pane believes the brain's local environment drives capillary changes, impacting brain plasticity and further contributing to disease progression. They will use cutting-edge 3D visualization techniques to map neurovascular structure and identify regions with the most extensive remodeling in a model of PWS at different life stages. Following this, they will employ functional ultrasound imaging to assess neurovascular coupling (NVC) — the mechanism by which neurovascular function matches neuronal activity — allowing them to pinpoint where and when NVC alterations occur during PWS progression. Finally, they will profile the cell types, genes, and pathways in the remodeled areas, identifying potential preclinical targets for therapeutic intervention.
Lay Abstract
This proposal aims to demonstrate that structural changes in brain capillaries are central to the metabolic and neurophysiological issues seen in Prader-Willi Syndrome (PWS). Our central hypothesis is that alterations in the brain's vascular network exacerbate metabolic and neurophysiological dysfunction in PWS. We believe the brain's local environment drives capillary changes, impacting brain plasticity and further contributing to disease progression.
We will use cutting-edge 3D visualization techniques to test this hypothesis, mapping neurovascular structure and identifying regions with the most extensive remodeling in a model of PWS at different live stages. Following this, we will employ functional ultrasound imaging to assess neurovascular coupling (NVC)—the mechanism by which neurovascular function matches neuronal activity—allowing us to pinpoint where and when NVC alterations occur during PWS progression. Finally, we will profile the cell types, genes, and pathways in the remodeled areas, identifying potential preclinical targets for therapeutic intervention.
Our approach is groundbreaking due to the novel tools we've developed to visualize and study gene expression in the brain's vasculature. These tools allow us to analyze neurovascular alterations and their impact on neuronal activity, influencing behavior. These insights could pave the way for new therapeutic approaches to treat PWS.