Noninvasive optogenetics

Nanoparticles in the brain turned heat into light and made mice afraid

Daria Spasskaya, N+1

Researchers working in the field of optogenetics have learned how to noninvasively activate neurons that can be excited by light. Instead of optical fiber, which must be injected into the brain through a hole in the skull, model animals were injected with nanoparticles capable of converting infrared radiation into blue spectrum radiation that excites modified neurons. To control the activity of neurons and stimulate the deep parts of the brain, thus, it is now possible directly through the tissues using an infrared laser. The study is published in Science (Chen et al., Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics).

Optogenetics allows for directional control of the activity of individual groups of neurons expressing channelorhodopsin (ChR). This protein begins to pass current under the influence of blue light and causes depolarization of the neuron membrane. Since biological tissues do not transmit visible spectrum light, to control neurons in the brain, model animals (most often mice) have to inject optical fiber.

Scientists from the Japanese RIKEN Institute for Brain Research, in collaboration with colleagues from the National Universities of Tokyo and Singapore, have proposed an alternative way to activate neurons using ultraconversion nanoparticles. These nanoparticles containing metal ions from a number of lanthanides convert several photons with a long wavelength into one photon with a higher energy, and, accordingly, a shorter wavelength. Such nanoparticles make it possible to use infrared radiation to stimulate the deep parts of the brain, which penetrates well into the tissues, and "on the spot" turns into visible light.

Diagram of the stimulation process (drawings from the press release of RIKEN Deep-brain exploration with nanomaterial - VM).

The researchers prepared nanoparticles with a metal core and coated them with silicon oxide to avoid the toxic effect caused by the contact of the core with tissues. After confirming the safety of the presence of nanoparticles in the nervous tissue, mice were injected with a genetic construct encoding channelorhodopsin into the region of the midbrain responsible for dopamine synthesis. Then nanoparticles were injected into the same area of the brain, after which this area was exposed to near-infrared radiation (980 nanometers) transcranially (through the skull). A control fiber-optic sensor detected radiation of the desired wavelength in the brain (corresponding to blue light), and at the physiological level, the researchers observed activation of dopamine neurons and dopamine synthesis in this zone.

Noninvasive activation of mouse neurons in the ventral region of the tire (VTA), the reward center of the brain. The blue light-sensitive channelorhodopsin (ChR2) is colored green and is located on both sides of the VTA, however, blue-colored ultraconversion nanoparticles (UCNP) were introduced only on the right. Near infrared light (NIR) affected both sides, but activated the expression of the CFOs (red dots) gene induced by activity only from the side where the nanoparticles were injected – VM.

In the following experiments, using nanoparticles, the researchers successfully synchronized the activity of neurons in the hippocampus of sleeping animals and "forced" them to generate a theta rhythm. The scientists also managed to reproduce a more impressive experiment on awake mice, previously implemented using "classical" optogenetics. By placing mice in a cage in which they were electrocuted, scientists recorded the "scheme" of activation of hippocampal neurons involved in the formation of bad memories and the associated reaction – fear. By selectively activating these neurons with infrared radiation, scientists caused fear in mice even in a safe place. Conversion nanoparticles have previously been used to activate neurons in cell culture and on Danio rerio fish. However, in mammals, the success of the non-invasive approach and the ability to even control animal behavior with its help was shown for the first time. Theoretically, noninvasive activation of brain regions can also be used in humans – for example, deep stimulation with electrodes is currently being considered as a promising means of therapy for Parkinson's disease and major depressive disorder. The main obstacle to the introduction of this method into the clinic is the need for genetic modification of neurons, so for now optogenetics in all its forms is the lot of laboratory animals.

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