Mice models show that injecting crushed scintillators that emit visible light into brain cells upon shining X-rays can activate opsins that control neural functions and decision making.
Wireless brain control is no longer the future, it is happening now. Scientists have finally discovered a way to exercise remote optogenetic control of neural functions at any depth of the brain with minimal toxicity using X-rays and scintillators.
Optogenetics, as its name suggests, is a combination of genetic and optical methods that allows for the precise control of neurons in the brain. Conventionally, this approach involves injecting neurons with genetically modified, light-sensitive membrane proteins called opsins. These proteins can be activated by shining light of specific wavelengths, after which the light can be converted into electrical signals to activate neurons.
In most experiments, scientists would inject these proteins to manipulate the excitability and activation of neurons, and learn how neurons regulate circuit dynamics, plasticity, and even behaviour. In recent years, scientists have tried to bring the technique into clinical practice to aid treatments for neurological diseases. However, the technique remains an investigative tool rather than a therapeutic avenue due to some major technical limitations.
One such challenge is finding a way to explore deep brain regions without compromising safety. Optogenetic procedures, in general, require the invasive implantation of optical fibres that are connected to a light source to stimulate light to the neurons. However, reaching the deep areas of the brain using this method often leads to extensive tissue damage, light toxicity, and other harmful effects of thermal irradiation.
To minimise this damage, researchers have devised a minimally invasive alternative – injecting into target tissues and neurons nano or microparticles that emit visible light in response to near-infrared irradiation. This technique allows scientists to overcome the issue of safety, but not without cost. Near-infrared irradiation is limited to penetrating only mere millimetres of tissues, thus preventing deep tissue analysis. Safety and deep exploration, it seemed, could not go hand-in-hand. That is, until recently.
Neuroscientists from Japan’s Fujita Health University have finally solved this dilemma with the help of X-rays, which can penetrate deep regions of the brain without damaging radio-sensitive cells in the body. Although opsins do not respond to X-rays, they found a way to work around this problem by using scintillators, which can convert radiation into visible light.
Professor Takayuki Yamashita, one of the lead authors of the study, explained, “Scintillators, which emit visible light when irradiated with X-rays, have widely been used in X-ray inspection machines and CT scans, but their applications in biology have been limited. This work is the first application of scintillators to behavioural neuroscience.”
In their novel study, the team first synthesised inorganic scintillator crystals, which emit yellow light. They then crushed these crystals and injected the microparticles into mice brain cells. Upon irradiating X-rays onto the dissected head of a mouse, they found that the X-rays could pass through the skin, skull, and brain tissue of the mouse. The microparticles also successfully emitted yellow light, which activated the opsins for excitation and inhibition of neurons. Tests with live mice indicated similar results.
Given these optimistic findings, the researchers sought to further explore the extent of neural control with their method, specifically if the control of neural function by X-rays and opsins could induce behavioural changes. To test this idea, they performed a conditioned place preference test wherein mice had to choose between two compartments, one of which was exposed to X-ray radiation. The mice either had excitatory opsins or inhibitory opsins injected into their neurons which govern this type of behaviour.
Prior to the X-ray irradiation, it was reported that no mice displayed any form of preference for a compartment. However, after being exposed to X-rays, the mice with excitatory opsins demonstrated an increased preference for the X-ray irradiated compartment, whereas the mice with inhibitory opsins opted for the non-irradiated compartment. In terms of safety, the scientists have assured that the scintillators are biocompatible and non-toxic even when used for long-term implantation.
With these promising results, scintillator-based optogenetics are expected turn the vast potential applications of optogenetics into clinical practice. From modulating neurons for research to treatment of neurological disorders, the non-invasive and wireless nature of this new technique is hoped to overcome the challenges of present methods.
“There are many biomedical technologies that use light to control protein functions. However, these technologies have not been easy to apply to deep tissues owing to the low penetration of stimulating light into the tissue. In contrast, our technology is almost unconstrained by the depth of the tissue,” said Professor Yamashita.
Source: Matsubara et al. (2021). Remote control of neural function by X-ray-induced scintillation. Nature Communications, 12, 4478.