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Noninvasive chemical approach controls deep region of the brain in mice

In mice, surgery-free technique inhibits region implicated in memory formation

by Cici Zhang
July 12, 2018 | A version of this story appeared in Volume 96, Issue 29

A diagram shows the three-step approach to controlling deep parts of the brain without surgery: opening the blood-brain barrier, delivering a special receptor, and controlling the receptor with a small molecule.
Credit: Nat. Biomed. Eng.
With the help of ultrasound, harmless viruses carrying the code for a special receptor protein cross the blood-brain barrier. After the receptors are situated on the targeted neurons, the neurons can be turned on or off by adding the synthetic drug CNO.

Deep-brain regions are implicated in movement disorders, obsessive-compulsive disorder, and other conditions. Despite many advances in neuroscience, tools remain limited for reaching deeper regions of the brain without surgery. Now, a team led by Mikhail Shapiro at California Institute of Technology reports an approach in which ultrasound, genetic engineering, and a synthetic drug work together to control deep parts of the brain in a selective and noninvasive way. The researchers tested their technology in mice, but their ultimate goal is to use it as an alternative to surgery for humans (Nat. Biomed. Eng. 2018, DOI: 10.1038/s41551-018-0258-2).

Currently, physicians treat certain brain diseases by stimulating deep-brain regions with implanted electrodes, Shapiro says. He and his coworkers used a nonsurgical approach to turn off neurons in a deep-brain region known as the hippocampus, which is key for memory formation. In the mouse study, the researchers first opened the blood-brain barrier, which keeps out harmful substances but also poses challenges for drug delivery. They injected microbubbles into the mice’s bloodstream and triggered microbubble vibration with ultrasound waves, generating a temporary opening in a specific brain region. Then, the team delivered harmless virus particles that carry genetic instructions for adding special receptors to the neurons they wished to target. Once the receptor proteins were situated in the neurons of interest, the researchers administered a synthetic drug called clozapine-N-oxide (CNO) to selectively activate or inhibit the activity of the modified neurons. Mice with the inhibited neurons no longer showed fear in an environment in which they previously received a mild electric shock. The results suggest that fear memories were prevented from forming.

Shapiro says the approach could lead to “localized therapy that’s not only noninvasive but also convenient.” After the ultrasound procedure, in theory, whenever the patient or the physician needs to control the targeted part of the brain, the patient can just take the drug, he says. As a next step, Shapiro says they will test mice engineered to have an epilepsy-like condition to see if the technology could treat severe seizures without removing disease-affected brain tissues.

Elisa Konofagou, a biomedical engineer at Columbia University who studies ultrasound for the treatment of brain diseases, says more animal research is needed to see the long-term effects of the approach.


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