Visualizing the "Invisible" Molecular Dynamics within Brain Tissue

Brain functions are sustained by highly precise (nanometer-scale) and dynamic (millisecond-scale) molecular processes, with synaptic transmission being a prime example. Even subtle alterations in these dynamics can trigger disease onset. Moreover, molecular dynamics are profoundly influenced by the complex environment of brain tissue, where diverse cell types are intricately interwoven. To address this, we have developed novel fluorescent probes for molecules such as glutamate, inositol trisphosphate, and luminal Ca²⁺ in the endoplasmic reticulum. Using high-resolution imaging in ex vivo and in vivo brain tissues, we have uncovered previously unknown mechanisms of signal transduction (see representative papers).

Until recently, our observations were constrained by the optical diffraction limit. However, advances in super-resolution microscopy have revealed that the dynamics of a small number of protein molecules at the nanometer scale form the very foundation of brain function. Building on this, we have developed new fluorescent labeling techniques and optical systems capable of achieving exceptionally high signal-to-background ratios even within brain tissue. This has enabled us to establish a method for single-molecule imaging within brain tissue (manuscript in preparation).

Currently, we are further advancing and applying this single-molecule imaging technology. Ongoing projects include developing in vivo single-molecule imaging, visualizing the earliest pathological processes of neurodegenerative diseases by capturing the dynamics of aggregation-prone proteins, and extending these approaches to drug evaluation and drug discovery research.