NeuroNex News
February 2023, Issue #1
For decades, the neuroscience community has worked to better understand the mouse brain—largely because its genetic profile is almost identical to the human brain. However, the mouse brain is still poorly understood due to its extreme complexity, the rapid speed at which neurons process information, and the difficulties associated with imaging the brain in general. As a solution, the NeuroNex project “Accelerating the Development of Genetically Encoded Voltage Indicators,” performed at Baylor College of Medicine’s Department of Neuroscience, is developing fluorescent biosensors that can report neuronal activity signals even faster than one thousandth of a second. The project has adopted multidisciplinary approaches, combining techniques from synthetic biology, electrical engineering, optics, computational biology, and neuroscience. "Previous biosensors were too slow to track neuronal signals, resulting in slurred recordings," says Project PI François St-Pierre. "Our optimized sensors are now sufficiently fast and sensitive to properly eavesdrop on what neurons are saying to one another."
Meet Alex Kunin. Currently an assistant professor in the Department of Mathematics at Creighton University, Kunin was drawn to the field of neuroscience in his first year in grad school when he watched a presentation on how specific neurons known as place cells are activated when an animal enters a particular place in its environment referred to as a place field. It was this arrangement of place fields and their relationship to specific patterns of neural activity—all of which can be studied using combinatorial geometry—that fascinated Kunin. "My mind was blown: first, by the very existence of place cells, and two, by the application of one of my favorite areas of mathematics to neuroscience." Kunin is part of the NeuroNex project, “Accelerating the Development of Genetically Encoded Voltage Indicators,” where he’s currently developing methods to study network structure, specifically looking at relationships between individual brain cells—such as correlations in their firing rates—to infer features most relevant in determining connectivity. There have been some challenges along the way, however. Coming from the world of "pure" math, where one can assume ideal conditions, it took Kunin a while to get used to the realities of data, which are often messy and incomplete. Over time, however, he has grown to appreciate the efficacy of mathematical models in providing valuable insight despite that inherent messiness of real data. “I have been amazed by the unreasonable effectiveness and ineffectiveness of mathematics in neuroscience,” says Kunin. At Creighton University, Kunin will help revamp a couple of courses in the Math Department. The position involves a mix of teaching and research—an ideal combination for Kunin. In his spare time, Kunin works on legos, origami, and designing 3D printed sculptures. And for aspiring neuroscientists, he has these words of wisdom: "Learn as much linear algebra as you can. You won't regret it."
In 2019, researchers at Brown and Central Michigan Universities introduced a non-invasive method to potentially treat spinal cord injuries in rats using light naturally emitted by living organisms—a phenomenon referred to as bioluminescence—as a way to fire up specifically targeted neurons below the site of injury. The team is part of the NeuroNex program, Bioluminescence for Optimal Brain Control and Imaging. More recently, they refined their original method and published their findings in the International Journal of Molecular Sciences. (This research is funded by NSF’s NeuroNex Program and the Craig H. Neilsen Foundation.) Bioluminescence occurs as a result of a chemical reaction between a molecule luciferin and an enzyme luciferase. As part of the treatment, researchers tether the luciferase to light-sensitive ion channels, generating what’s referred to as luminopsins or LMOs. While in 2019, researchers turned to luciferase found in ocean crustaceans, in this recent study they used the algae Scherffelia dubia, which has a more light-sensitive ion channel than the crustaceans. “By using this new generation of luminopsins we were able to improve on our previous results in terms of being less invasive,” says Eric Petersen, an assistant professor at Central Michigan University College of Medicine and senior author on the recent paper that introduced the improved luminopsin, dubbed LMO3.2. In this latest effort, researchers began by injecting two groups of eight rats each with adeno-associated virus or AAV into the lower region of their spinal cord (illustration, top right). The virus causes the targeted cells to express the luminopsin. Three weeks after the virus had been injected, researchers induced a severe spinal injury in all 16 rats by dropping a 10-gram weight from a height of 25 millimeters, which paralyzed their hind legs. Eight of those rats were then treated with a luciferase substrate, in this case coelenterazine or CTZ, every other day for two weeks to stimulate the neurons expressing LMO3.2. The other eight were given a vehicle solution which consists of just the solvent that is used to deliver the CTZ (illustration, bottom left). When looking at the recovery rate after two weeks of treatment and another three weeks of follow-up (illustration, bottom right), researchers found that 75 percent of the rats treated with CTZ recovered to an extent where they could consistently walk without dragging their feet, stumbling, or falling over while the vehicle-treated animals did not reach that level of consistent weight-supported walking. For this team of researchers, refinement is key. “We’re still working on producing better luminopsins that will require lower doses of their substrate to work,” says Petersen. “I’m interested in improving the method to apply it to different areas of research and, hopefully one day, as an actual treatment would be the end goal.”
What’s NeuroNex?
NeuroNex brings together researchers working across disciplines into a coherent network to develop innovative, accessible, and shared technologies and approaches, as well as theoretical frameworks and computational modeling to advance understanding of brain function across organizational levels and a diversity of species.
NeuroNex News is a quarterly e-newsletter, produced by the NeuroNex Web Team. Contact us at [email protected] with questions, concerns, or submissions.
