The extracellular matrix as a dynamic regulator of brain function and plasticity.

The brain extracellular matrix (ECM) is a dynamic and complex scaffold that not only provides structural support but also plays a key role in regulating synaptic plasticity, axonal regeneration, and cell signaling throughout development and into adulthood. This review focuses on the major components of the brain ECM-including structural proteins (e.g., collagen, elastin), adhesion glycoproteins (e.g., laminin, fibronectin, tenascin), and proteoglycans (e.g., aggrecan, brevican), with an emphasis on their region-specific expression patterns and dynamic changes during development and disease. We explore the role of the ECM in neurodegenerative diseases, psychiatric disorders, and chronic pain, and examine its interactions with glial cells (particularly astrocytes and microglia), which actively remodel the ECM through secretion of matrix-degrading enzymes such as matrix metalloproteinases (MMPs). This review also explores the unique challenges of studying the brain ECM, including its specialized composition and the technical limitations of existing methods. We discuss how recent advances in imaging, mass spectrometry, and omics technologies may provide new insights into ECM dynamics. Finally, we consider future directions, highlighting the potential of AI-based modeling and multi-omics integration to reveal the role of the ECM in brain function and dysfunction and inform a novel therapeutic strategy for neurological and psychiatric diseases.