Team : NAGERL
The extracellular space of the brain: a multi-modal analysis from nano-structure to in vivo function
Project Leader(s): TBD
The extracellular space (ECS) forms an important but understudied frontier in neuroscience. It consists of the narrow gaps that surround all brain cells, which are filled with interstitial fluid and extracellular matrix molecules, occupying around one fifth of the volume of the brain. Even though all extracellular signaling molecules and nutrients must transit through the ECS to reach their targets, we know very little about the shape and dynamics of this brain compartment, or its influence on brain function. Although the ECS has received much less attention than neuronal and glial networks, it plays a fundamental functional role in brain health and disease, serving as a reservoir of ions for electrical activity and providing an essential microenvironment for the well-being of cells and brain homeostasis. Based on pioneering theoretical and biophysical studies, we know the diffusivity and geometry of the ECS are major determinants of how molecules (endogenous substances or medical drugs) can spread around the brain or get cleared from it. However, mapping the biophysical landscape of the ECS with enough spatial resolution in live brain tissue has been impossible to accomplish until now for lack of appropriate tools. Bringing together a team of leading researchers, this multidisciplinary project studies key properties of the ECS, focusing on its dynamic organization, its role in material transport (in brain perivascular spaces and parenchyma) and its impact on brain function at the cellular and systems level. To this end, we develop several innovative investigative tools that will allow us to image and manipulate key aspects of the ECS, and to study its structure and function in brain slices, in vivo and in silico. Specifically, we (1) engineer novel chemical tools to label hyaluronan (HA) and to manipulate its biological activity, (2) develop super-resolution microscopy technology to study impact of ECS on synaptic function in brain slices and to enable ECS visualization in the intact brain in vivo, (3) make biophysical measurements to quantify diffusion of molecules through the ECS, (4) investigate ECS control of ‘glymphatic’ function in the sleep-wake cycle, (5) construct morphologically realistic mathematical models to simulate substance transport through the ECS. This combination of methodologies enables us to better understand how this brain compartment influences brain physiology, focusing on single neuron function and sleep.