Measuring Activity From More Neurons in More Areas Over Weeks to Months Will Increase Understanding of Complex Cognitive Processes
Scientists at UC San Francisco have developed an innovative tool to peer into the secret life of brain cells. The new recording device has the potential to measure the electrical activity of over 1000 individual neurons in real time from 16 different locations in the rat brain, and it can remain in place for many months, producing the most comprehensive and longest-lasting recordings ever. The researchers hope to use the device to learn more about how memories form, and how past experiences influence decisions.
When measuring brain activity, the two most critical considerations are time and space, on both a micro and macro scale. Scientists need to record the activity of individual neurons, which are smaller than the width of a human hair, but they also would like to know how widely separated brain regions interact. They must capture neural impulses that transpire over just a fraction of a second, but in order to track how the brain changes over time they have to record for days, weeks, or even months.
“The technology to achieve adequate scale, flexibility, and longevity basically didn't exist,” said Loren Frank, PhD, a professor of physiology, member of the UCSF Weill Institute for Neurosciences and Howard Hughes Medical Institute investigator at UCSF. “So we decided to try to build something where we could do multi-regional recordings, as well as recordings for really long periods so we could watch the brain change.”
Described in the November 27, 2018 issue of Neuron, the new tool—which took Frank’s lab seven years to build—is organized into 16 individual fork-shaped recording modules. Each fork can be placed in a different location in the brain and even moved to a new position if need be. The forks have 4 tines that contain 16 electrodes each, totaling 64 electrodes on every fork—1024 electrodes in all.
Most current recording devices are made out of wire or silicon, which are harder materials that can damage the soft tissue of the brain. The new technology, developed in collaboration with scientists at Lawrence Livermore National Laboratory, uses a plastic-like material called polymer that is more malleable. The electrodes can move with the brain to remain in contact with the neurons they’re recording from without damaging the soft tissue. Thanks to this adaptation, the device can track the activity of individual neurons across many days and can continue to measure single-neuron activity for at least 11 months.
“The brain has the consistency of Jell-O, so in order to keep the electrodes in close proximity to the neurons, we want them to be soft so that they can move with the brain,” explains Jason Chung, an MD/PhD student in Frank’s lab who helped develop the technology. “A conventional silicon electrode is more rigid; you can think of it like a toothpick sitting in Jell-O, and when the Jell-O moves around you’re shearing through neural tissue. But if you have something flexible like the polymer, it can move with the brain.”
Established recording devices can track a few individual neurons in one area for a couple of days but don’t have the scale or adaptability that researchers need to understand complex processes like learning, memory, and decision-making. Even the newest technologies, which have proven capable of recording large groups of neurons for up to four months, haven’t matched the longevity and flexibility of the new system to measure activity from so many different regions at one time.
“Important activity in the brain doesn’t occur in just one place, it happens across many areas all connected together; it’s a very distributed circuit. As a result, we really need to be able to understand how different parts of the brain are interacting—how they’re talking with one another,” said Frank. “Our goal was to build a system that we could basically assemble out of parts: where individual recording components would let us target different areas and then be able to reassign those components based on our experimental needs.”
In a demonstration of the new tool’s power, the scientists targeted 16 different areas in four widely separated parts of the brain—the hippocampus, ventral striatum, orbitofrontal cortex, and medial prefrontal cortex—to better understand how activity in one area of the brain might influence activity in another. They discovered that these four regions were coordinated during a type of activity called a sharp wave-ripple, which is important in memory formation and retrieval, as well as planning.
The device is currently only available for use in rats, but Frank is collaborating with 20 labs around the country to adapt the technology for research in other animals. Chung, who is training to be a neurosurgeon, hopes to one day use similar tools and techniques to improve care for human patients.
“My goal is to leverage what we learn from animal models and basic science and try to apply that to human disease,” he said. “With the precision offered by this tool, we can get a more detailed picture of the brain, which could drive richer brain-machine interfaces for paralyzed or disabled patients or other clinical applications that may not be possible now.”
Authors: Additional authors on the paper include: Hannah Joo, Jiang Lan Fan, Daniel Liu, Charlotte Geaghan-Breiner, and Hexin Liang of UCSF; Alex Barnett, PhD, Jeremy Magland, PhD, and Leslie Greengard, MD, PhD, of the Flatiron Institute; Mattias Karlsson, PhD, and Magnus Karlsson, PhD, of SpikeGadgets; and Supin Chen, PhD, Kye Lee, Jeanine Pebbles, Angela Tooker, PhD, and Vanessa Tolosa, PhD, of Lawrence Livermore National Laboratory.
Funding: This work was supported by the National Institute of Neurological Disorders and Stroke (U01NS090537) and the National Institute of Mental Health (F30MH109292).
Conflicts: Chung and Frank are inventors on a pending patent related to the work described here. Karlsson and Karlsson are co-founders of SpikeGadgets, the company that built the acquisition hardware.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.