Lighting up the depths of the brain

Neuroscience is in the grips of transformation. In the quest to understand the brain’s messenger systems, researchers no longer have to rely on crude electrodes to prod and probe. Instead, they study the brain using highly focused laser beams of visible light that stimulate neural circuits in living, even moving, animals. This technique, known as optogenetics, was developed about a decade ago and has resulted in a huge growth in neuroscience’s output.

However, there is a fundamental problem with using light on brain matter—it cannot travel far before it is absorbed or scattered, which has limited the reach of optogenetics to about half a millimeter into the brain. To overcome this restriction, neuroscientists insert optical fibers (see image), but these fibers sometimes damage surrounding brain tissue. Now, in a study published in Science, Thomas McHugh of the RIKEN Center for Brain Science and his co-workers have found a way around this problem: they are using a near-infrared beam and ‘upconverting’ it to visible light in the relevant brain region by injecting sophisticated nanoparticles¹.

Near-infrared light can travel considerably further into the brain than visible light. But near-infrared light cannot stimulate neurons, so McHugh’s team had to devise a means to convert it into visible light within the brain.

Converting high-energy ultraviolet light into lower energy visible light is fairly simple—scientists have a plethora of fluorescent dyes at their disposal that do this. But going in the opposite direction and changing low-energy infrared light into more energetic visible light is more of a challenge. Two or more particles, or photons, of infrared light need to pool their energies to produce a single photon of visible light. The process requires special particles known as upconversion nanoparticles, so-named because they can convert low-energy photons into higher energy ones.

It was at this point that the expertise and connections of Shuo Chen, a postdoctoral researcher in McHugh’s lab, proved invaluable. “Chen did a PhD in chemistry, and he knew people working on particle synthesis,” says McHugh. “He came to my lab to do optogenetics and said ‘I think there are ways we can improve this tool if we talk to the right chemists.’”

Chen connected McHugh with chemists at the National University of Singapore who specialize in making upconversion nanoparticles. When McHugh’s team injected these nanoparticles close to a brain region of interest, they were able to convert the near-infrared light into visible light, which in turn stimulated neurons. This process has extended the reach of optogenetics to about 4.5 millimeters—roughly a tenfold improvement on the conventional method and about the same depth as that of a mouse brain.

Using this method, the team has already been able to stimulate the release of dopamine, trigger the recall of memories and modify mouse fear responses.

Wolfgang Parak, who co-authored an accompanying article on the paper’s findings in Science, is confident of the importance of overcoming the visible light “dilemma”. Parak, who is from the Center of Hybrid Nanostructures at the University of Hamburg, Germany, and his two co-authors, chose to focus their article on the possible future applications of the method to control neurological issues in human patients, such as those with Parkinson’s disease. Without it, they note that altering brain activity in a “substantial and targeted way” requires a complex tangle of electrodes. Due to this and the size of conventional electrode arrays, they point out that up until now optogenetics has had “severely limited clinical applications”.