The glowing path to watching single-cell activity in living brains
A decade ago, a team of researchers dared to imagine illuminating brain activity from inside the brain itself using bioluminescent light.
“We asked, what if we could light up the brain from within?” remarked Christopher Moore, a brain science professor at Brown University. “Traditional methods rely on fluorescence to measure activity or to trigger it. But lasers and extensive hardware come with downsides and limited success rates. Bioluminescence offered a cleaner, less invasive alternative.”
With strong support from a National Science Foundation grant, Brown’s Bioluminescence Hub at the Carney Institute for Brain Science launched in 2017, born from collaborations among Moore (associate director of the Carney Institute), Diane Lipscombe (the institute’s director), Ute Hochgeschwender of Central Michigan University, and Nathan Shaner of UC San Diego.
Their mission was bold: to create neuroscience tools that empower nervous-system cells to generate and respond to light.
In a Nature Methods study, the team unveiled a bioluminescent tool designed to monitor activity at high speed at the level of individual cells and even subcellular regions. Named Ca2+-Bioluminescence Activity Monitor—or CaBLAM for short—the device enables multi-hour recordings in mice and zebrafish without the need for external illumination.
Moore credited Shaner, an associate professor of neuroscience and pharmacology at UC San Diego, for leading the development of this molecular system. “CaBLAM is truly remarkable,” Moore said. “It lives up to its name.”
Tracking ongoing brain activity is essential for understanding how organisms function. Today, many researchers rely on fluorescent calcium indicators to visualize neural activity.
Moore explained the basic idea: fluorescence works by exciting a molecule with external light and detecting the emitted light whose wavelength shifts depending on calcium levels. While useful, fluorescence has notable drawbacks for brain research. Prolonged exposure to strong external light can damage cells. Intense illumination can also cause photobleaching, where the fluorescent molecule loses its ability to emit light over time. Additionally, the required hardware—lasers and optical fibers—demands more invasive procedures.
Bioluminescent probes, in contrast, generate light through an enzymatic reaction without bright external illumination, avoiding photobleaching and reducing risk to brain tissue.
“Brain tissue naturally emits some light when illuminated externally, creating background noise,” Shaner noted. “Moreover, light scattering by brain tissue blurs both incoming light and the emitted signal, making deep-brain imaging dim and fuzzy. When neurons are engineered to glow on their own, they stand out against a dark backdrop with minimal interference. Bioluminescence lets us watch the cells’ own light, essentially giving them headlights that are easier to track through tissue.”
The concept of brain activity measurement via bioluminescence has been discussed for decades, Moore said, but the key breakthrough was amplifying the light brightness enough for detailed imaging of single-cell activity—something not achieved before CaBLAM.
The CaBLAM system can monitor a single neuron in a living, behaving animal and even resolve activity within subcellular compartments. In one demonstration, researchers recorded five consecutive hours of neural activity, a timescale unattainable with traditional fluorescence limits.
“For studying complex behavior or learning, bioluminescence lets you capture the whole process with less hardware,” Moore noted.
CaBLAM is part of a broader effort at the Bioluminescence Hub to develop new ways to control and observe brain activity. One project explores using living cells to emit bursts of light that a neighboring cell can detect—effectively enabling neurons to communicate optically, a process Moore describes as “rewiring the brain with light.” Another line of work aims to harness calcium signals to steer cellular activity. As these ideas evolved, it became clear that they depended on brighter, more reliable calcium sensors, which has become a central focus.
Moore emphasized the Hub’s role in assembling essential building blocks to advance the field.
Looking ahead, he hopes CaBLAM will extend beyond the brain to illuminate activity in other parts of the body, broadening our view of how neural and bodily systems coordinate. “This advance opens up new possibilities for observing how the brain and body work together, including concurrent activity across multiple regions,” he said.
The project showcases the power of collaborative science. At least 34 researchers from Brown, Central Michigan University, UC San Diego, UCLA, and New York University contributed to the CaBLAM effort, supported by funding from the National Institutes of Health, the National Science Foundation, and the Paul G. Allen Family Foundation.
