Sub-second multi-channel magnetic control of select neural circuits in behaving flies

Abstract

Precisely timed activation of genetically targeted cells is a powerful tool for studying neural circuits and controlling cell-based therapies. Magnetic control of cell activity or “magnetogenetics” using magnetic nanoparticle heating of temperature-sensitive ion channels enables remote, non-invasive activation of neurons for deep-tissue applications and studies of freely behaving animals. However, the in vivo response time of thermal magnetogenetics is currently tens of seconds, which prevents the precise temporal modulation of neural activity similar to light-based optogenetics. Moreover, magnetogenetics has not provided a means to selectively activate multiple channels to drive behavior. Here we demonstrate that by combining magnetic nanoparticles with a rate-sensitive thermoreceptor (TRPA1-A) it is possible to achieve sub-second behavioral responses in Drosophila melanogaster. Furthermore, by tuning the properties of magnetic nanoparticles to respond to different magnetic field strengths and frequencies, we can achieve fast, multi-channel stimulation, analogous to optogenetic stimulation with different wavelengths of light. These results bring magnetogenetics closer to the temporal resolution and multiplexed stimulation possible with optogenetics while maintaining the minimal invasiveness and deep-tissue stimulation only possible by magnetic control.

Self-rectifying magnetoelectric metamaterials enable precisely timed remote neural stimulation and restoration of sensory motor functions

“…We found that the MNMs successfully bridge the sciatic nerve gap and enable nerve signals to activate the distal muscle groups with latencies of less than 5 ms (Fig 4C). This response time is approximately 120-fold faster than any previously reported remote neural stimulation using magnetic materials ( 6 ). Unlike existing magnetic materials used for neural stimulation, we show high temporal control with our MNMs, demonstrated by both the short latency between pulse generator and the EMG response (4.06 +/- 0.209 ms) as well as the ability to drive neural responses at frequencies up to 10 Hz (Fig 4C, Fig S5).…”

“…However, the cells and proteins in our body have very weak magnetic properties; thus, for magnetic fields to stimulate a biological response, researchers typically use high-field strengths in excess of 1 T that are generated by pulsed magnetics (1) or magnetic materials that convert a weak magnetic stimulus (typically less than 100 mT) into a form of energy that can stimulate nearby cells. Indeed, this materials-based approach offers superior selectivity because one can target a specific area for stimulation by limiting the location of the magnetic materials, or one can combine the magnetic materials with genetically modified cells to achieve cell-type specific neural stimulation (2)(3)(4)(5)(6)(7). A materials-based magnetic stimulation technique that could achieve millisecond timing would enable numerous neurotherapeutic applications and research applications that require neuromodulation to be precisely timed with sensory stimuli and behavior (8); however, existing magnetic materials have fallen well short of millisecond temporal precision.…”

“…A materials-based magnetic stimulation technique that could achieve millisecond timing would enable numerous neurotherapeutic applications and research applications that require neuromodulation to be precisely timed with sensory stimuli and behavior (8); however, existing magnetic materials have fallen well short of millisecond temporal precision. For example, magnetic heating of superparamagnetic nanoparticles can stimulate neurons that express thermoreceptors (2)(3)(4)(5) with behavioral response times approaching 500 ms (6) or trigger the release of drugs that cause a behavioral response with a latency of several seconds (7). Mechanical displacement of magnetic nanoparticles can also stimulate neural activity via mechanoreceptors (9,10), but the response times are several seconds in vivo (11).…”