An Upconversion Nanoparticle Enables Near Infrared-Optogenetic Manipulation of the Caenorhabditis elegans Motor Circuit

Abstract

Near-infrared (NIR) light penetrates tissue deeply, but its application to motor behavior stimulation has been limited by the lack of known genetic NIR light-responsive sensors. We designed and synthesized a Yb 3+ /Er 3+ /Ca 2+ -based lanthanide-doped upconversion nanoparticle (UCNP) that effectively converts 808 nm NIR light to green light emission. This UCNP is compatible with Chrimson, a cation channel activated by green light; as such, it can be used in the optogenetic manipulation of the motor behaviors of Caenorhabditis elegans. We show that this UCNP effectively activates Chrimson-expressing, inhibitory GABAergic motor neurons, leading to reduced action potential firing in the body wall muscle and resulting in locomotion inhibition. The UCNP also activates the excitatory glutamatergic DVC interneuron, leading to potentiated muscle action potential bursts and active reversal locomotion. Moreover, this UCNP exhibits negligible toxicity in neural development, growth, and reproduction, and the NIR energy required to elicit these behavioral and physiological responses does not activate the animal's temperature response. This study shows that UCNP provides a useful integrated optogenetic toolset, which may have wide applications in other experimental systems.

Upconversion Nanoparticles–Based Multiplex Protein Activation to Neuron Ablation for Locomotion Regulation

“…To assess whether the UCNPs potentiate cell killing by simultaneously activating both miniSOG and Chrimson under NIR light, we choose C. elegans DVC neuron as an exemplary neuron to perform the experiments, in view that it is a single, unilateral excitatory glutamatergic interneuron that regulates the backward locomotion 8a,16. With representative tail localization of the DVC soma in dorsorectal ganglion, a long ventral neurite outgrows from soma to the nerve ring (NR) in the head ( Figure A).…”

“…Lanthanide‐doped upconversion nanoparticles (UCNPs) have gained significant research interests in optogenetics due to their capability of converting tissue‐penetrable near‐infrared (NIR) light into programmable ultraviolet (UV) to NIR emissions . By carefully modulation of lanthanide nanoarchitecture and precisely selection of lanthanide dopants, their emissions can be finely tuned to match the working spectrum of established optogenetic light‐sensitive proteins, such as miniSOG (excited at ≈470 nm), NpHR (excited at ≈590 nm), or Chrimson (excited at ≈610 nm) 8a,b,d,g,9. Consequently, when coupled with UCNPs, neuron activities can be indirectly regulated by NIR irradiation and to control the locomotion behavior in C. elegans or mice 8a,d,f.…”

“…By carefully modulation of lanthanide nanoarchitecture and precisely selection of lanthanide dopants, their emissions can be finely tuned to match the working spectrum of established optogenetic light‐sensitive proteins, such as miniSOG (excited at ≈470 nm), NpHR (excited at ≈590 nm), or Chrimson (excited at ≈610 nm) 8a,b,d,g,9. Consequently, when coupled with UCNPs, neuron activities can be indirectly regulated by NIR irradiation and to control the locomotion behavior in C. elegans or mice 8a,d,f. However, current UCNPs–based optogenetic technology mainly focuses on utilizing single wavelength emission from nanoparticles to stimulate the light‐sensitive proteins, which largely limits the activation efficiency.…”

Theoretical optimization of high-frequency optogenetic spiking of red-shifted very fast-Chrimson-expressing neurons

“…57 In another recent study, Yb 3þ ∕Er 3þ ∕Ca 2þ -based lanthanide-doped UCNP has been shown to effectively activate Chrimson-expressing, inhibitory GABAergic motor neurons, leading to a reduced action potential firing in the body wall muscle of C. elegans and resulting in locomotion inhibition. 58 This UCNP provides a useful integrated optogenetic toolset for wide applications, as it exhibits negligible toxicity in neural development, growth, and reproduction, along with the nonactivation of the animal's temperature response with the NIR energy required to elicit behavioral and physiological responses. Using it with vf-Chrimson may lead to better NIR optogenetic manipulation of motor circuits in various organisms.…”

Advanced Near‐Infrared Light for Monitoring and Modulating the Spatiotemporal Dynamics of Cell Functions in Living Systems

“…In another interesting study, Ao and colleagues studied the movement behavior control of Caenorhabditis elegan by Yb 3+ /Er 3+ /Ca 2+ ‐based lanthanide‐doped UCNPs. [ 134 ] They found that the uranium‐doped UCNP effectively activated Chrimson (a green‐activated cation channel) and inhibited GABAergic motor neurons during 808 nm NIR light irradiation, thereby reducing the action potential of body wall muscle discharge and inhibiting the movement of nematodes. Thanks to the deep penetration of NIR‐Ⅱ light (1000–1700 nm), UCNP‐mediated optogenetics have also been used to spur deep brain neurons in living animals.…”