Sonogenetics is a non-invasive approach to activating neurons in Caenorhabditis elegans

Abstract

A major challenge in neuroscience is to reliably activate individual neurons, particularly those in deeper brain regions. Current optogenetic approaches require invasive surgical procedures to deliver light of specific wavelengths to target cells in order to activate or silence them. Here, we demonstrate the use of low-pressure ultrasound as a non-invasive trigger to activate specific ultrasonically-sensitized neurons in the nematode, Caenorhabditis elegans. We first show that wild-type animals are insensitive to low pressure ultrasound and require gas-filled microbubbles to transduce the ultrasound wave. We find that neuron-specific misexpression of TRP-4, the pore-forming subunit of a mechanotransduction channel, sensitizes neurons to ultrasound stimulus resulting in motor outputs. Furthermore, we use this approach to manipulate the function of sensory neurons and interneurons and identify a role for the PVD sensory neurons in modifying locomotory behaviors. We suggest this method can be broadly applied to manipulate cellular functions in vivo.

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

“…Stretch-sensitive channels in neurons respond to the shockwaves from pFUS+MB and modulate the influx of cations (e.g., Ca +2 ) into cells. Lowintensity FUS effects on MB in solution located outside nematodes expressing stretch-sensitive cationic channels resulted in altered behavior and activated neurons following Ca +2 influx into cells (55). Low-intensity FUS alone did not induce neuronal activation or alter behavior in the nematodes.…”

The Body Acoustic: Ultrasonic Neuromodulation for Translational Medicine

“…Given the acoustic impedance presented by the gaseous core of a microbubble (and likewise in endogenous gas bodies), these microbubbles can cause backscattering of a US wave, which lends itself to their use as a contrast agent for ultrasonic imaging applications. Additionally, these microbubbles can act as force multipliers during US-induced cavitation, affecting changes in membrane permeability through induced fluid microstreaming in the extracellular media, in an acoustic intensity-dependent manner [Sirsi and Borden, 2009;Ibsen et al, 2015]. A potential limitation to the use of microbubbles is that under sufficiently high acoustic intensities, destructive cavitation could occur and cause tissue damage in the focal area.…”

“…One of the most cutting-edge applications of ultrasonic NM to date is in 'sonogenetics', a method of manipulating a discrete neuronal population with US, microbubbles, and endogenously expressed TRP chan- nels [Ibsen et al, 2015]. These researchers demonstrated that the nematode, Caenorhabditis elegans , could be manipulated by US to engage in escape responses typically observed in response to noxious or dangerous stimuli ( fig.…”

“…Additionally, the expression of TRP-4 channels in different neuronal subtypes of the nematodes showed markedly improved responses to US stimulation versus wildtype nematodes, owing to the mechanosensitive properties of these pore-forming channels and corresponding changes in ion flux across the membrane [Venkatachalam and Montell, 2007], and implicating the importance of mechanosensing in US responses. These channels responded in an acoustic pressure-dependent manner when tested at 0.41, 0.47, and 0.6 MPa [Ibsen et al, 2015]. Combined with the microbubbles, TRP expression and US stimulation were shown to be feasible for the modulation of discrete neuronal populations with a high resolution and at low ultrasonic intensities in freely behaving organisms.…”

“…Combined with the microbubbles, TRP expression and US stimulation were shown to be feasible for the modulation of discrete neuronal populations with a high resolution and at low ultrasonic intensities in freely behaving organisms. The authors also noted that there is no indication of a TRP channel found in the mammalian brain, making them a promising option for sensitizing neurons to US, but only with suitable genetic manipulation of the human neurons, which has yet to be clinically demonstrated in vivo [Ibsen et al, 2015].…”