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Stanford researchers track neural activity in real time

Two teams of Stanford scientists have created long-sought-after neuroscience tools that allow researchers to observe living neurons signal to each other in real time.

The studies, led by postdoctoral scholars Francois St-Pierre (from Assistant Professor of Pediatrics Michael Lin’s lab) and Yiyang Gong (from Associate Professor of Biology Mark Schnitzer’s lab), were published April 22 in “Nature Neuroscience” and “Nature Communications,” respectively.

Professor Michael Lin's lab led one of the two teams who developed new neural imaging tools. Courtesy of Michael Lin.

Professor Michael Lin’s lab led one of the two Stanford teams who developed new neural imaging tools. Courtesy of Michael Lin.

Both studies featured the use of fluorescent protein voltage sensors, which can be inserted into specific groups of brain cells and which emit light when the nerves fire off signals. These sensors offer faster kinetics and higher brightness than preexisting imaging tools.

Existing methods to detect signaling between neurons make use of genetically-encoded fluorescent calcium indicators, which do not provide a direct readout of membrane potential changes. Limitations of calcium imaging include an inability to track individual action potentials in many fast-spiking cell types, which affects the accuracy of the reporting of neuronal activity.

The high-fidelity optical reporting offered by these newly-developed protein voltage sensors allow for monitoring of genetically-defined neuronal circuits without the requirement of direct chemical access.

“The challenge of voltage sensing has always been to get a sensor that is bright enough and has high enough dynamic range in response to voltage in the physiological range,” Lin explained.

In addition to high speed and high spatial resolution, the sensor itself needs to respond quickly to membrane potential changes.

One technique scientists use to study electrical signaling is patch clamping, which allows for the study of single or multiple ion channels in excitable cells. Instead of using patch clamping, drug developers can use these new tools to look at the effects of drugs on neuronal signaling.

“Wouldn’t it be great if instead of having a contact method, you could just use light as an output to see if your compound had an effect or not?” St-Pierre mused.

These protein voltage sensors also work in neurons in a petri dish. Drug developers could test the effectiveness of drugs targeting diseases like Alzheimer’s and Parkinson’s by observing in real time the way a drug affects nerve firings.

Gong described the two labs’ joint developments as the latest effort to achieve accurate optical reporting of electrical activity in neuronal populations, a long-standing goal in neuroscience.

“Our field is somewhat akin to guided guessing,” Gong said. “There have been incremental developments on how to make these tools bright so they have higher signal for our eyes or a camera to see.”

The money for their project came from a Stanford Bio-X seed grant, which funds high-risk – and high reward – projects.

The teams have worked to further refine their proteins to respond uniquely to different types of neurons, so researchers will be able to isolate the effects of certain cell types. Lin and Schnitzer received additional funding through a Bio-X Neuroventures grant, and said they anticipate their latest invention enabling further exciting applications.

Contact Julia Turan at jturan ‘at’ stanford ‘dot’ edu.


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