New tool reveals details of the microscopic brain structures between neurons

Between and around the billions of neurons in the human brain is an equally vital scaffold, the extracellular matrix (ECM). An interlinked net of proteins and sugars that surrounds brain cells, the ECM is more than simple structural support; changes in the ECM can regulate complex brain functions including memory, learning, and behavior. But studies of the brain’s ECM have been limited by the lack of tools to observe dynamic changes to its structure.

Now, a new genetic labeling tool developed by University of Utah Health researchers Igal Sterin, PhD, and Sungjin Park, PhD, has revealed new patterns in brain ECM in mice, including differences in the amount of matrix deposited on different types of neurons. A major advantage of the tool is that it can detect changes in the ECM over time, giving new insights into how the brain develops.

The new tool has two main parts: a protein that binds to the main ingredients of the brain ECM, fused to another protein that irreversibly sticks to a variety of synthetic fluorescent dyes. When scientists introduced the tool into neurons, it bound to the surrounding matrix; then, they added a fluorescent dye to make matrix structures visible. Using this tool, the researchers were able to watch as ECM was deposited over time in cultured rodent brain cells, making out dense clusters of matrix that appeared on only certain neurons and at different times.

The researchers were also able to measure changes in brain ECM in mice by adding different fluorescent dyes at different times. They could infer that ECM structures that were marked by the second dye, but not the first, had developed in the time between the two dyes were added.

The scientists hope that this tool will open the door to many further studies of how the ECM contributes to brain function in complex ways. “In the brain, the ECM regulates neuronal plasticity and cognitive function, but its structural features remain poorly understood,” Park says. “By using our longitudinal genetic tool to track ECM dynamics, we can visualize how neurons assemble and remodel ECM during development, cognitive processes, and aging.”

These results published in the Journal of Neuroscience as “Dynamic organization of neuronal extracellular matrix revealed by HaloTag-HAPLN1” on September 9, 2024.