One-Step Optogenetics for Hacking the Nervous System

drawing of mouse with optogentics probe
Photo-illustration: MIT

Engineers have taken one of biotech’s hottest tools—optogenetics—and made it better. The 12-year-old technique, which enables scientists to control brain cells with light, typically requires a multi-step process and several surgeries on animal models. Polina Anikeeva at the Massachusetts Institute of Technology (MIT) and her colleagues came up with an engineering solution that combines those steps into one, and improves the function of the device. The group described their invention today in the journal Nature Neuroscience.

Optogenetics enables researchers to hack into the body’s electrical system with far more precision than traditional electrical stimulation. The technique involves genetically altering specific neurons so that they can be turned on or off with a simple flash of light.

The tool is useful for figuring out the functions of neural circuits—fire up a select few brain cells and see how the body responds. A mouse might run faster or eat more or become aggressive, depending on which neurons were manipulated.

So far, optogenetics research has been limited to animal models. That’s partly because the tool is invasive and the process rather protracted. First the animal’s brain cells must be genetically altered. One way to do that is to incorporate a light-sensitizing gene into a viral vector—the non-infectious kind—and inject it into the brain using a small syringe.

The genetic modifications cause the neurons to produce proteins and other cellular elements that, when exposed to light, allow ions to enter. An influx of sodium ions will activate the neuron, causing it to fire, and starting a chain reaction among the neurons connected to it. An influx of chloride ions, on the other hand, will inhibit the neuron.

Once the genetic modifications have taken hold, researchers implant a device that delivers light—usually with silica optical fibers or light-emitting diodes—to the modified cells. Then researchers can start turning neurons on and off and correlating it with behavioral changes.

In a third step, the resulting electrical activity in the brain is recorded. That information helps scientists be sure of which neurons are firing or not firing during behavioral experiments. But recording requires implantation of electrodes that, in combination with light sources, makes the experiment too cumbersome, so scientists often skip it.

Each step—gene delivery, light implant, and recording electrodes—typically requires a separate surgical procedure. And all three have to be directed to exactly the same spot in the brain. “You can be pretty sure” that you got it in the same place, “but not 100 percent sure,” says Anikeeva at MIT, who led the study.

MIT’s probe integrates all three pieces into one device implanted with one surgery. The key was the electrode: a custom-designed, highly conductive, very thin polymer composite, which can record and transmit neural signals. The material turned out to be so conductive that MIT was able to make the electrodes super small—small enough to fit six of them in the probe.

The group made the conductive polymer using layers of polyethylene sprinkled with graphite. “It’s kind of like a layered cake,” says Anikeeva. “We literally sprinkled on the graphite like sugar,” and melted and pressed the layers together in a high temperature vacuum.

The smallness of the electrodes left room for the other two elements: a polymer waveguide to deliver light and two microfluidics channels to deliver the gene-carrying virus. All together, the cylinder probe was still half the diameter of typical optogenetics implants, and more flexible.

photo of mouse with one-step optogentics implant
Photo: MIT

Anikeeva’s group tested the device in mice in a set of experiments. In one study, they delivered a light-sensitive gene construct into an area of the mouse brain called the medial prefrontal cortex, where activating neurons is known to make mice run faster. Sure enough, with Anikeeva’s probe implanted, the mice darted around their confines faster than the control group.

German and Swiss researchers four years ago developed an all-in-one optogenetics probe, and published a report on it in the journal Lab on a Chip. But that design hasn’t been adopted by many optogenetics research labs. “We loved that paper,” says Anikeeva. “It was a really great pioneering demonstration,” but the design process isn’t conducive to production in large quantities, and the materials aren’t well suited for optogenetics, she says.

By contrast, Anikeeva’s probe is made by a thermal drawing process, in which they fabricate a large scale version of the device, and the heat and stretch the structure hundreds of meters long. The thread-thin fiber can then be chopped into hundreds of research-sized pieces.

Anikeeva says that since she first presented at a conference in July 2016 an early version of the probe, she has received several requests from researchers wanting to use the device for a variety of applications: studying nerve circuitry linked to anxiety and addiction, peripheral nerves, and even motor nerves used to control prosthetics. Anikeeva plans to make the tool freely available. “We will send fibers to anyone who wants them,” she says.

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