Remote control of neural function by X-ray-induced scintillation

Takanori Matsubara,Sayaka Takemoto-Kimura,Satoshi P Tsunoda,Junichiro Yoshimoto,Noriaki Kawaguchi,Hitoshi Takizawa,Takayuki Yamashita,Maiko Sezaki,Shuhei Ueda,Takayuki Yanagida,Hideki Kandori,Takashi Nakano,Shin-Ichiro Horigane,Akihiro Yamanaka

doi:10.1038/s41467-021-24717-1

Abstract

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), can effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles are non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level is sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables minimally invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.

Highlights

Scintillators emit visible luminescence when irradiated with X-rays
Non-optical forms of energy delivery to control the activities of specific neuronal populations using magnetothermal[17] and ultrasonic[18] stimulation have been explored; these approaches are associated with a significantly reduced time resolution compared with optogenetics and are currently restricted by limited compatibility with free behavior
X-ray irradiation did not increase the temperature of tissues, whereas NIR illumination with a conventional optogenetic stimulation protocol caused striking tissue heating (Supplementary Fig. 2)

Summary

Introduction

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. The application of optogenetics to deep brain regions usually requires the invasive implantation of optical fibers tethered to an external light source because the stimulating light (wavelength: ~430–610 nm) used to activate light-sensitive proteins is heavily scattered and absorbed by tissues[1] These tethered fiber optics, widely employed, are known to pose diverse problems, including tissue damage, neuroinflammatory responses, phototoxicity and thermal effects upon irradiation, as well as physical restriction of animal movement[8,9,10,11]. The concept that scintillators could potentially serve as optogenetic actuators has already been proposed[19,20] It has not yet been proven whether scintillation induced by X-rays can effectively manipulate neural functions in behaving animals by activating light-sensitive proteins. This work demonstrates that X-rays can be used to control the function of cells at any tissue depth, expanding the range of X-ray applications in biology and medicine

Methods

Results

Conclusion