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Hidden network of cells in the brain through intercellular nanotubes: where are they, what do they do, and how can we control them?
The recent discovery of dendritic nanotubes suggests that there could be an additional layer of nanoscale intercellular network in the brain for direct transports from ions and pathogenic proteins to organelles such as mitochondria beyond the synaptic connectome (Chang et al., 2025, Science). We focus on the extended connectome at the neuron-glia interface in the brain. Leveraging our expertise in super-resolution imaging in animal models, we investigate the existence of hidden networks of nanotubes, their contribution to brain physiology and diseases, and ways to modulate these networks based on molecular-level dissection of their structures. We focus on supportive network formation for neuronal resilience and its deterioration in neurodegenerative diseases, especially Alzheimer's Disease (AD) using AD mouse models and patient postmortem brains. For more insight, please see the lecture above on the discovery of dendritic nanotubes (BRIC webinar, October 2025).
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Where and when does a synapse begin?
Many of the proteins that make up a synapse are not unique to neurons. Other cell types carry much of the same molecular machinery. What sets neurons apart is their ability to gather these components at exactly the right place and time, and that is what turns a simple point of contact into a working synapse. How does a neuron decide where to build each of its thousands of synapses, and what has to happen first? To answer this, we watch synapses as they form in living neurons, using advanced optical imaging, including super-resolution microscopy, together with tools to precisely manipulate cells. We follow how the cytoskeleton, local protein-making machinery, and the mitochondria that power it are organized at a future synapse site, and in what order. By uncovering the rules behind synapse placement, we hope to understand how brain circuits are wired, and whether the same principles shape other forms of cell-to-cell communication, such as those through intercellular nanotubes. Ultimately we aim to leverage the basic understanding to develop a therapeutic approach to neurodevelopmental disorders.
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How does the symbiotic behavior of cells sustain multicellular organisms?
Genes have been called "selfish," yet cells sharing the same genome can be remarkably selfless. Cellular donation of organelles from healthy to damaged cells, even between heterotypic cells, suggests that multicellular organisms have evolved symbiotic cellular behaviors that remain poorly understood. We examine the significance of nanotube-mediated mitochondrial transfer outside the nervous system, which serves for systemic resource distribution in tissues, and its pathological alteration in degenerative diseases and cancers. Ultimately we test a bold hypothesis of a hidden 'connectome' of cells through nanotubes outside the brain and leverage the finding to suggest a new paradigm for regenerative approaches to the diseases.
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How can we develop multidisciplinary & quantitative approaches to map nanoscale cellular networks in tissues?
Studying nanoscopic cellular connections embedded in the mass of cells in tissues requires continued effort to overcome technological challenges. Our lab aims to develop multidisciplinary and innovative approaches to map those connection networks and modulate them specifically, expanding our current expertise at the interface of biophysics, cell biology, and neuroscience accelerated by computational methods, including AI-driven imaging analysis.
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