Molecular Cell Biology Division of Multicelluar Circuit Dynamics

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OUTLINE

For more details, please visit the laboratory’s own website.

RESEARCH PROJECTS

For more details, please visit the laboratory’s own website.

1.Elucidating the Physiological Functions of Glial Cells

a. Novel physiological functions of microglia

Microglia are the resident immune cells of the central nervous system (CNS). Historically, research has focused on their role in pathological states, as they become activated during psychiatric and neurological disorders. However, their physiological functions in the healthy brain remained largely unknown.

Using in vivo imaging with two-photon microscopy, we have demonstrated that physiological microglia regularly contact synapses (the junctions between neurons) in an activity-dependent manner. We also discovered that once a synapse becomes abnormal, the duration of microglial contact increases, leading to the eventual elimination of that synapse (Wake et al., 2009).

Furthermore, we revealed that microglia modulate synaptic activity through these contacts, promoting the synchrony of neuronal activity and thereby influencing higher brain functions such as learning (Akiyoshi et al., 2018). During development, we found that microglia contact neuronal dendrites to promote the formation of immature synapses, facilitating specific neural circuit connectivity (Miyamoto et al., 2016). Additionally, we showed that microglia contribute to the functional enhancement of remaining senses following congenital vision loss (Hashimoto et al., 2023).

Based on these findings, we have proposed that microglia contribute significantly to the development of psychiatric disorders (Wake et al., 2013, Miyamoto et al., 2015). Our current research focuses on microglial interactions with blood vessels, their abnormalities in psychiatric disorders like schizophrenia, and their specific roles in Alzheimer’s disease.

b. Activity-dependent myelination

Oligodendrocytes myelinate axons, a process that can increase the propagation speed of action potentials by approximately 50-fold.

We have identified the molecular basis within oligodendrocytes that governs activity-dependent myelination (Wake et al., 2011) and characterized the morphological features supporting this process (Wake et al., 2015). By combining two-photon microscopy with imaging mass spectrometry, we have also identified specific molecules and lipid groups that change alongside neural circuit remodeling during motor learning (Kato et al., 2023). Currently, we are using two-photon microscopy and electrophysiological techniques to investigate how activity-dependent myelination contributes to neuronal synchrony and motor learning.

2. Development of Holographic Microscopy

Our laboratory has been dedicated to in vivo imaging using two-photon microscopy to visualize the structure and function of the brain in living mice. This allows us to observe the activity of neuronal populations during motor and sensory learning, perform mathematical analyses, and identify abnormalities in disease states.

To manipulate these neuronal activities, optogenetic methods have advanced significantly. As we attempted to ""correct"" abnormal neuronal population activity based on our imaging data, we recognized the need for optical manipulation with higher spatiotemporal resolution. Consequently, we are developing advanced microscopes in collaboration with the Graduate Schools of System Informatics, Science, and Engineering at our university, as well as the National Institute for Physiological Sciences (NIPS), RIKEN, and industry partners such as Nikon and Santec (Quan et al., 2018).

By integrating holographic projection technology into our microscopes, we can shape laser beams to enable various patterns of light projection. This allows us to induce activity in specific neurons (Okada et al., 2021) and precisely label targeted cells (Tsuji et al., 2025).

3. Interdisciplinary Analysis of the Brain Microenvironment and Cancer Cell Interactions

We investigate the mechanisms of metastatic brain tumors—specifically, how cancer cells originating in other organs reach and colonize the brain—and the resulting immune responses.

Microglia are the primary immune cells within the brain parenchyma and are responsible for the initial immune response. We have established techniques for the long-term observation of cancer cells and microglia in the living brain using two-photon microscopy in animal models. This has allowed us to capture the exact moments when invading cancer cells attempt to colonize the brain parenchyma or are eliminated by microglial intervention, revealing the diverse fates of cancer cells within the brain.

Furthermore, we have elucidated the mechanisms by which cancer cells evade ""patrolling"" by the immune system, including microglia, and have identified key factors that regulate brain metastasis and serve as potential therapeutic targets (Tsuji et al., 2025).

BIBLIOGRAPHY