Researchers use a combination of ultrasound waves, genetic engineering, and synthetic drugs to switch specific neurons on and off in mice.
Researchers at Caltech have designed a noninvasive method to control specific neural circuits in the mouse brain. The technique, published earlier this week (July 9) in Nature Biomedical Engineering, combines ultrasound waves with genetic engineering and the administration of designer compounds to selectively activate or inhibit neurons. Although currently only tested in mice, the approach could offer a novel way to administer therapy to regions of the human brain that are difficult to access using surgery.
“By using sound waves and known genetic techniques, we can, for the first time, noninvasively control specific brain regions and cell types as well as the timing of when neurons are switched on or off,” study coauthor Mikhail Shapiro says in a statement.
While several emerging methods in neuroscience allow researchers to manipulate brain circuits, most “require invasive techniques such as stereotaxic surgery, which can damage tissue and initiate a long-lasting immune response,” note neuroscientists Caroline Menard and Scott Russo of Quebec City’s Université Laval and the Icahn School of Medicine at Mount Sinai, respectively, in an accompanying News and Views article. “Also, conventional pharmacological approaches lack the spatial, temporal and cell-type specificity required to treat the brain, and can lead to deleterious side effects.”
To get around these issues, the Caltech team first injected microbubbles into mice’s blood vessels, and then zapped the bubbles with ultrasound waves at specific regions in the brain to create temporary, local openings in the blood-brain barrier. The researchers then took advantage of those openings to sneak in a viral vector carrying a gene coding for an engineered type of protein known as designer receptors exclusively activated by designer drugs (DREADDs)—in this case, a receptor that would respond to the synthetic drug clozapine-N-oxide (CNO).
Once the genes had been delivered, the team was able to activate or inhibit neurons, depending on the type of DREADD being expressed in the cells, by injecting the mice with CNO. In a proof-of-concept assay, the researchers used the technique to selectively inhibit neurons in the hippocampus, temporarily blocking the animals’ ability to form memories of a painful stimulus.
“This method is reversible,” study coauthor Jerzy Szablowski notes in the statement. “You can administer a drug to turn off neural cells of interest, but, with time, those cells will turn back on.”
The researchers hope to test the technique, which they’ve dubbed acoustically targeted chemogenetics (ATAC), in animal models of brain diseases, according to the statement. Shapiro notes that the method “is a combination of technologies, each of which have been used in animals and are being advanced into the clinic. Because of this, we are further along in our development process than we would be if we started from scratch.”
However, Elisa Konofagou, a biomedical engineer at Columbia University, tells C&EN that the technique will need to go through more animal research in order to properly understand any long-term effects.