Bioluminescent Tool Reveals Single-Cell Brain Activity
Ten years ago, a group of researchers conceived a surprisingly bright idea: use bioluminescent light to visualize how individual brain cells behave in real time.
“We asked ourselves, what if we could illuminate the brain from the inside out?” explained Christopher Moore, a Brown University brain-science professor. “Traditional approaches shine external light on the brain to measure activity—often via fluorescence—or to drive cellular activity to test roles. But shining lasers into the brain has drawbacks: complex hardware, invasive procedures, and limited success rates. Bioluminescence offered a cleaner alternative.”
With substantial support from the National Science Foundation, Brown’s Bioluminescence Hub at the Carney Institute for Brain Science launched in 2017, emerging from collaborations among Moore (co-director of the Carney Institute), Diane Lipscombe (the institute’s director), Ute Hochgeschwender (Central Michigan University), and Nathan Shaner (UC San Diego).
Their aim was to develop and share neuroscience tools that empower nervous-system cells to produce and respond to light.
In a Nature Methods study, the team introduced a bioluminescence tool named Ca2+BioLuminescence Activity Monitor—CaBLAM for short. This device records single-cell and subcellular activity at high speeds in living mice and zebrafish, supports multi-hour sessions, and eliminates the need for external illumination.
Moore credited Shaner, an associate professor of neuroscience and pharmacology at UC San Diego, with leading the creation of the molecular system that became CaBLAM. “CaBLAM is an extraordinary molecule that Nathan built,” Moore remarked. “It truly lives up to its name.”
Tracking ongoing neural activity is fundamental to understanding how organisms function, Moore noted. The prevailing method relies on fluorescence-based, genetically encoded calcium indicators.
“Fluorescence works by bombarding a sample with light and detecting emitted light at a different wavelength,” explained Moore, who heads the Bioluminescence Hub. “If you tailor this process to be calcium-sensitive, you can generate signals that shift in color or intensity depending on calcium presence, yielding a bright readout.”
Yet fluorescence has notable drawbacks for brain monitoring. First, prolonged exposure to strong external light can damage cells. Second, intense illumination can cause photobleaching, reducing light output over time. Third, using fluorescence often requires invasive hardware such as lasers and optical fibers to reach deep tissues.
Bioluminescent light generation—where enzymes catalyze light emission from a small molecule—offers several advantages. Since it does not rely on bright external light, there’s no risk of photobleaching, and it minimizes phototoxic effects, making it safer for brain health.
Bioluminescence also enhances visibility. Brain tissue can glow faintly on its own when illuminated externally, creating background noise. Additionally, brain tissue scatters light, which blurs incoming and outgoing signals, yielding dimmer, fuzzier images deeper in the brain. Engineered neurons that glow autonomously stand out against this dark backdrop, acting like built-in headlights. With bioluminescence, researchers only observe the emitted light, simplifying detection even through scattering tissue.
Although the concept of imaging brain activity with bioluminescence has existed for decades, no one had yet achieved sufficient brightness for detailed imaging of single-cell activity—until CaBLAM.
CaBLAM’s development marked a turning point, Moore said. It enables researchers to observe single neurons firing in real time within a living animal, even within subcellular structures, and to capture five hours of continuous data—something fluorescence-based methods struggle to do because of bleaching and exposure limits.
For studying complex behaviors or learning, bioluminescence offers a more continuous, lower-hardware approach, he added.
CaBLAM is part of a broader initiative by the Bioluminescence Hub to expand methods for controlling and observing brain activity. One project envisions using living cells to emit light that a neighboring cell detects, effectively enabling neuronal communication via light. Other efforts aim to use calcium signals to directly control cellular activity. As these ideas matured, the demand for brighter, more sensitive calcium sensors grew—a central focus of the hub’s research agenda.
Moore emphasized that the hub’s success rests on team science. At least 34 researchers from Brown, Central Michigan University, UC San Diego, UCLA, and New York University contributed to CaBLAM, with funding from the NIH, NSF, and the Paul G. Allen Family Foundation.
Looking forward, Moore hopes CaBLAM will prove useful beyond neuroscience, potentially enabling simultaneous activity mapping across multiple body regions. He views this achievement as a testament to collaborative science and the power of bright, accessible tools for understanding living systems.
Source:
Journal reference:
