A team of scientists has developed a new bioluminescent tool that enables detailed observation of single-cell activity in living brains. The tool, known as the Ca2+ BioLuminescence Activity Monitor (CaBLAM), was created through a collaboration led by researchers at Brown University’s Carney Institute for Brain Science, Central Michigan University, and the University of California San Diego.
Christopher Moore, professor of brain science at Brown University and associate director of the Carney Institute, explained the origins of the project: "We started thinking: 'What if we could light up the brain from the inside?'" He noted that traditional methods often use fluorescence to measure or manipulate brain activity but can require complex equipment and may have limited success rates. “We figured we could use bioluminescence instead.”
The Bioluminescence Hub at Brown's Carney Institute began in 2017 with support from a major National Science Foundation grant. Its goal has been to develop neuroscience tools that allow nervous system cells to both generate and respond to light.
The research team recently published their findings in Nature Methods, describing how CaBLAM can record single-cell and subcellular activity at high speeds in animal models such as mice and zebrafish. This approach allows for multi-hour recordings without needing external light sources.
Moore highlighted the contribution of Nathan Shaner, associate professor at U.C. San Diego: "CaBLAM is a really amazing molecule that Nathan created," Moore said. "It lives up to its name."
Measuring ongoing activity in living brain cells is crucial for understanding biological functions. The most common method uses genetically encoded calcium-ion indicators with fluorescence imaging. As Moore described: "In the way fluorescence works, you shine light beams at something, and you get a different wavelength of light beams back... You can make that process calcium-sensitive so you can get proteins that will shift back a different amount or different color of light, depending on whether or not calcium is present, with a bright signal."
However, this method has drawbacks such as potential cell damage from prolonged exposure to external light, photobleaching (where molecules lose their ability to emit light), and invasive hardware requirements.
Bioluminescent probes offer several advantages because they do not rely on external illumination. There is no risk of photobleaching or phototoxicity, making them safer for brain health.
Nathan Shaner explained another benefit: "Brain tissue already glows faintly on its own when hit by external light, creating background noise... The brain does not naturally produce bioluminescence, so when engineered neurons glow on their own, they stand out against a dark background with almost no interference. And with bioluminescence, the brain cells act like their own headlights: You only have to watch the light coming out, which is much easier to see even when scattered through tissue."
Moore noted that while using bioluminescence in neuroscience had been considered before, achieving sufficient brightness for detailed imaging was only possible now with CaBLAM. "The current paper is exciting for a lot of reasons," Moore said. "These new molecules have provided, for the first time, the ability to see single cells independently activated, almost as if you're using a very special, sensitive movie camera to record brain activity while it's happening."
The team demonstrated that CaBLAM could capture five continuous hours of single-neuron activity in live animals—something not possible with previous fluorescence-based techniques.
"For studying complex behavior or learning, bioluminescence allows one to capture the entire process, with less hardware involved," Moore said.
This development is part of broader efforts by the Bioluminescence Hub to create new ways to control and observe neural processes. Other projects include enabling neurons to communicate via bursts of light and developing calcium-based methods for controlling cellular activity.
"We made sure that as a center that's trying to push the field forward, we created the necessary component pieces," Moore said.
Looking ahead, Moore expressed hope that CaBLAM could be used beyond neuroscience applications: "This advance allows a whole new range of options for seeing how the brain and body work," he said, "including tracking activity in multiple parts of the body at once."
At least 34 researchers contributed from institutions including Brown University, Central Michigan University, U.C. San Diego, UCLA and New York University. Funding came from organizations such as the National Institutes of Health (NIH), National Science Foundation (NSF), and Paul G. Allen Family Foundation.
