What the scientists had was a lab version of The Dog That Didn’t Bark — or, if Sherlock Holmes were chronicling the experiment, The Mice That Didn’t Freeze.
One at a time, the 20 mice went into a little cage in a lab at Caltech and nosed around for three minutes, until a tone sounded — and the metal floor of the cage zapped them with a mild shock. Twice more — tone, zap; tone, zap — to teach each mouse that sound meant imminent pain. A day later, the mice proved themselves quick studies: When they heard the tone they froze, a classic fear response.
Except for the mice that kept nosing around. They had been given genes that caused neurons in their brain’s memories-making hippocampus to sprout receptors unknown in nature, but which scientists had carefully crafted to fire when exposed to a lab-made drug. When the Caltech scientists fed the mice the drug, the neurons followed the script: They fired, sending signals telling the hippocampus to stand down. As a result, memory formation also shut down, the mice didn’t learn that tone = zap, and they didn’t freeze when they heard the tone.
The study, described in a paper submitted to a journal, is only the latest advance in the booming field of brain control.
Formally called neuromodulation, the ability to precisely activate or silence brain neurons took off with the 2005 invention of optogenetics. That technique has two basic components: DNA is inserted into neurons via genetic engineering that makes them responsive to special light, and optical fibers are threaded into the brain of, usually, a lab mouse, allowing scientists to turn those neurons on and off at will merely by shining special blue-green light through the fibers.
“If you’re able to do optogenetics without implanting optical fibers, it creates whole new possibilities.”
Mikhail Shapiro, Caltech
Now Optogenetics 2.0 is adding to neuroscientists’ bag of brain-control tricks. In the Caltech study, neurotechnologist Mikhail Shapiro and his colleagues substituted designer drugs for the light in the original optogenetics. With such “chemogenetics,” giving a lab animal a simple lab-made molecule, and only that molecule, triggers the genetically engineered target neurons to fire. The scientists added an acoustic twist: Focused ultrasound opens up the blood-brain barrier and sends the genetic tweak to only certain neurons, in this case the hippocampus. They call it acoustically targeted chemogenetics.
In another advance, reported on Thursday in Science, researchers in Japan hauled optogenetics into the wireless era. Dispensing with the optical fibers that the original optogenetics needs to carry light to brain neurons, they simply shined light onto lab mice’s skulls. The targeted neurons fired at (scientists’) will.
Wireless optogenetics “is quite appealing and could be an important advance,” said Shapiro, who declined to speak about his own paper before it was published. “If you’re able to do avoid implanting optical fibers, it creates whole new possibilities.”
The original optogenetics, optical fibers and all, works well enough that hundreds of labs have made thousands of discoveries with it. They’ve identified the precise brain circuits for hunger, thirst, breathing, remembering, smelling, hearing, seeing, feeling, and hearing, and more.
If optogenetics is to become a therapy, however, optical fibers will almost certainly have to go, as suggested by the first clinical trials of optogenetics. Allergan has an early-stage one for the form of blindness called retinitis pigmentosa, and French biotech Gensight Biologics is planning something similar. But the eye is an easy target: Light can reach the target neurons directly — no optical fibers needed. That is not true of neurons deep in the brain.
Enter special nanoparticles, made of rare metals called lanthanides. Their superpower is converting infrared light, which easily penetrates the skulls and brains of mice and men, into the blue-green light that the genetically engineered neurons respond to. (The wireless technique is not totally non-invasive: It gets the nanoparticles to the desired spot in the brain by injecting them.)
The scientists, led by Thomas McHugh of the RIKEN Brain Science Institute outside Tokyo, used their Wi-Fi optogenetics to turn off hyper-excitable neurons that caused seizures in their mice. And they got it to work in the classic teach-mice-to-fear set-up: After mice learned that a particular box will give them an electric shock, shining light onto the animals’ skulls activated the precise hippocampal neurons encoding that memory. The mice froze in fear even in a different, safe box. That happened for up to two weeks, showing that the nanoparticles stayed put and kept working.
Besides dispensing with optical fibers, wireless optogenetics can manipulate brain areas beyond the reach of the standard version, McHugh said: “You can usually insert a fiber into the cortex without causing much damage, but if you want to go deeper into the brain, it’s challenging.”
Because it is less invasive, wireless optogenetics “might eventually lead the way for clinical applications to optically control neuronal dysfunctions, such as Parkinson’s disease or even paralysis,” Wolfgang Parak of the Institute of Nano Biomedicine and Engineering in Shanghai and co-authors wrote in a commentary on the paper. It’s “a big step toward noninvasive manipulation of brain activity.”
The closest thing to that manipulation today is deep brain stimulation to treat movement disorders including Parkinson’s disease, epilepsy, and chronic pain. But it requires surgery to insert electrodes, and has a small risk of stroke or infection.
With wireless optogenetics, it might one day be possible to treat Parkinson’s tremors “with on-demand optical stimulation of the relevant regions in the brain,” Panak said.
Look for a three-way race pitting chemogenetics against standard and wireless optogenetics, starting in research. Optogenetics works over a period of seconds; light hits the neuron, and it fires. That’s good for studying brain processes that work in the blink of an eye, such as perception. Chemogenetics can work for hours or days; as long as the lab-made molecule is sloshing around the brain, it can keep activating target neurons. That’s useful for long-term processes, such as the different stages of learning and memory.
For clinical use, anything that requires optical fibers is expected to increase cost, difficulty, and possibly the risk to patients. Until wireless optogenetics proves itself, chemogenetics has one clear edge. It requires only the injection of virus particles carrying genes that make neurons respond to whatever molecule scientists choose. Once the gene has been delivered, said Caltech’s Shapiro, “controlling the neurons is as easy as giving a pill.”