Ectopic expression of a mechanosensitive channel confers spatiotemporal resolution to ultrasound stimulations of neurons for visual restoration

Abstract

Remote and precisely controlled activation of the brain is a fundamental challenge in the development of brain–machine interfaces for neurological treatments. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain, especially after expressing ultrasound-sensitive proteins. But so far, no study has described an ultrasound-mediated activation strategy whose spatiotemporal resolution and acoustic intensity are compatible with the mandatory needs of brain–machine interfaces, particularly for visual restoration. Here we combined the expression of large-conductance mechanosensitive ion channels with uncustomary high-frequency ultrasonic stimulation to activate retinal or cortical neurons over millisecond durations at a spatiotemporal resolution and acoustic energy deposit compatible with vision restoration. The in vivo sonogenetic activation of the visual cortex generated a behaviour associated with light perception. Our findings demonstrate that sonogenetics can deliver millisecond pattern presentations via an approach less invasive than current brain–machine interfaces for visual restoration.

Force-Based Neuromodulation

“…29 In another application, the Picaud laboratory demonstrated the feasibility of sonogenetics for vision restoration by activating the retina and primary visual cortex expressing the mechanosensitive ion channel of large conductance (MscL; Figure 1e). 28 In the ex vivo retina, retinal ganglion cells responded to 15 MHz FUS with millisecond precision, following rhythms as high as 10 Hz, and exhibited submillimeter activation precision. In addition, sonogenetic stimulation in the primary visual cortex of rats showed spatial precision within 400 μm and a response rate that could follow a 13 Hz repetition rate.…”

“…Specifically, as a primary force-based stimulus, ultrasound has emerged as a powerful tool for noninvasive and transcranial neuromodulation, functioning effectively on its own . In combination with transgenic mechanosensitive channels, ultrasound enables neuron-type specific modulation while achieving deep tissue penetration, as demonstrated in the emerging “sonogenetics” method. − In addition, ultrasound can provide mechanical force to force-responsive nanotransducers, which convert the mechanical energy into localized light, heat, or electrical response, for neuromodulation. ,, Furthermore, as a secondary force-based stimulus, force-producing nanotransducers in response to an applied magnetic field and light can also achieve neuromodulation effects. ,, Specifically, mechanical forces produced by these nanotransducers, when applied to cell membranes, can induce action potentials through capacitive mechanisms or the direct activation of mechanosensitive ion channels. − In summary, mechanical force-based neuromodulation techniques, though less explored, show promise for developing noninvasive and nongenetic tools. In this Account, we aim to provide an overview of the general approaches in force-based neuromodulation.…”

Sonogenetics for Monitoring and Modulating Biomolecular Function by Ultrasound

“…Cadoni et al advanced the technology by fine-tuning the spatiotemporal resolution to a precision of 400 μm at a frequency of 15 MHz. [63] This significant breakthrough, in line with the stringent requirements of brain-machine interfaces, was the activation of neurons in the visual cortex of mice, generating a behavior indicative of light perception.…”

Ultrasound-Induced Cascade Amplification in a Mechanoluminescent Nanotransducer for Enhanced Sono-Optogenetic Deep Brain Stimulation

“…Moreover, X-ray-activated luminescent nanoparticles have been designed for remote and minimally invasive optogenetics, but the damage to tissues by X-ray radiation must be considered. , As alternatives to visible/NIR light and X-ray radiation with excellent penetration performance and safety profiles are magnetic field and focused ultrasound (FUS). Magnetic modulation with nanotransducers − and sonogenetic modulation by combining ultrasound with mechanosensitive ion channels − have been shown to function in deep neuronal tissue. Magnetic modulation approaches are generally slow, hypothesized to be due to latency in converting magnetic power to heating or mechanical force, which hampers their application in fast control of neuronal activity. ,,− On the other hand, while great progress has been reported in sonogenetics, the programmability of sonogenetics is still limited with respect to neural excitation in comparison to the comprehensive optogenetics toolbox that enables versatile control of neuronal excitation, inhibition, excitability, and precise activation frequency/kinetics. ,,, Therefore, it is most desirable to develop a minimally invasive and remote light delivery technology that could utilize the optogenetic toolbox for neuroscience research and clinical applications.…”