New method enables long-lasting imaging of rapid brain activity in single cells deep in the cortex

As you read these words, certain regions of your brain display a rapid wave of electrical activity in milliseconds. Visualizing and measuring this electrical activity is important for understanding how the brain allows us to see, move, behave or read these words. However, technological restrictions are delaying neuroscientists from achieving their goal of improving understanding of brain function.

Scientists at Baylor College of Medicine and collaborating institutions report in the journal Mobile a new sensor that allows neuroscientists to image brain activity without missing signals, for an extended duration, and deeper in the brain than before. This work paves the way for new discoveries about brain function in awake and active animals, both healthy ones and those with neurological conditions.

The Holy Grail of Neuroscience

“Not only is electrical activity in the brain very rapid, but it also involves a variety of cell styles that have different roles in brain computations,” said corresponding author Dr. Francois St-Pierre, assistant professor of neuroscience and McNair Scholar at Baylor. He is also an adjunct adjunct professor of electrical and computer science at Rice University. “Understanding how to noninvasively observe millisecond-fast electrical activity in individual neurons of specific cell styles in working animals has been challenging. Being able to do this has been the holy grail of neuroimaging.”

There are systems to measure electrical activity in the brain. “For example, the electrodes can register very fast activity, but they can’t tell what type of cells they’re listening to,” St-Pierre said.

Researchers are also using fluorescent proteins that respond to changes in calcium associated with electrical activity. “This form of sensor is fantastic for determining which neurons are active and which are not. However, they are very slow. They measure changes in pressure indirectly, thereby missing many key signals.”

The goal of St-Pierre and his colleagues was to combine the best of these methodologies – to develop a sensor capable of monitoring the activity of specific cell types while capturing fast brain signals. “We achieved this with a new generation of modified fluorescent proteins called genetically encoded stress indicators or GEVIs,” said St-Pierre.

Co-first authors — Zhuohe ( Harry) Liu. the typical method of non-invasive deep tissue imaging in neuroscience. “Using this system, we tested thousands of indicator variations and identified JEDI-2P, which is faster. said Liu, an electrical and computer engineering graduate student at Rice who works in St. Peter’s Laboratory.

“With JEDI-2P, we have solved three significant drawbacks of previous methods,” said Lu, a graduate student in Rice’s Systems, Synthetic, and Physical Biology (SSPB) program who works in the lab. of Saint-Pierre. “First, it allows us to track the electrical activity of a live animal for 40 minutes instead of a few minutes at the highest. Secondly. and third, we can image individual cells deeper in the brain because our indicator is bright and produces large signals in response to brain activity.”

Up Now, the researchers were limited to looking at the area of ​​the brain, “but most brain activity is obviously not limited to the first 40 microns below the area of the brain,” St-Pierre said. “Our methodology allows researchers to noninvasively monitor pressure signals in the deep layers of the cortex for the first time,” said Gou, a former member of the St-Pierre lab who is now in the graduate program. in Neuroscience at Baylor.

Baylor co-authors Dr. Andreas Tolias, Professor of Neuroscience, and Dr. Jacob Reimer, Assistant Professor of Neuroscience, demonstrated that JEDI- 2P can signal electrical activity in mice using imaging equipment available at many neuroimaging labs. Co-author Stéphane Dieudonné (École Normale Supérieure, France) showed deep and ultrafast detection of brain electrical signals in mice by monitoring JEDI-2P fluorescence with a rapid microscopy method called ULoVE.

The laboratories of co-authors Drs. Katrin Franke (group leader, University of Tübingen, Germany) and Tom Clandinin (Stanford University) showed how JEDI-2P could also be applied to image electrical activity in the retina and in flies, respectively. Taken together, this international collaborative effort demonstrated that the new technology could be easily deployed by neuroscience groups working in different animal models and using various microscopy techniques.

“In 2014, I gave a presentation at the Culture of Neuroscience meeting on the first version of this indicator and people were rolling their eyes. They believed that fast-rigidity imaging with fluorescent indicators would never be achievable in awake animals due to the huge system challenge of imaging activity at the millisecond scale,” St-Pierre said. . “Eight years later, we have achieved this goal. And there’s still room to upgrade the indicator – it won’t be the last JEDI! ”

Other contributors to this work include Vincent Villette, Kevin L. Colbert, Shujuan Lai, Sihui Guan, Michelle A. Land, Jihwan Lee, Tensae Assefa, Daniel R. Zollinger, Maria M. Korympidou, Anna L. Vlasits, Michelle M. Pang, Sharon Su, Changjia Cai, Emmanouil Froudarakis , Na Zhou, Saumil S. Patel, Cameron L. Smith, Annick Ayon, Pierre Bizouard, Jonathan Bradley and Andrea Giovannucci. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Rice University, École Normale Supérieure, University of Tübingen, Stanford University, College of North Carolina at Chapel Hill, North Carolina Point out College and the Foundation for Investigation and Hellas-Greece Technology.

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