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.

Magnetic nanomaterials for wireless thermal and mechanical neuromodulation

“…Using channels which respond to sudden temperature changes rather than a threshold temperature offer potentially a much-increased response time. One demonstration of this is the magnetothermal stimulation of dTrpA1 to evoke a sub-second behavioral response in Drosophila ( Figure 5 D) ( Sebesta et al., 2021 ). Using TREK1 potassium channel provides magnetothermal neuronal silencing with similarly decreased response time ( Figure 5 C) ( Liu et al., 2022 ).…”

“…Top: Wing opening due to magnetothermal activation of TRPA1. Bottom: Wing angle plots as a response to thermal stimulation and schematic of behavioral chamber (adopted from ( Sebesta et al., 2021 )). (E) Magnetomechanical stimulation of rodent behavior.…”

Multichannel power electronics and magnetic nanoparticles for selective thermal magnetogenetics

“…In contrast, the stimulation fields formed about 15 millimeters below the skull by conventional transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) have natural focality limits [11,12] due to the current spread and shunting for TES [13,14] and the fundamental depth-focality trade-off for TMS [15,16]. In addition, selective heating of magnetic nanoparticles using various frequency-amplitude combinations of the magnetic field has been achieved via variation of the size and coercivity of magnetic nanoparticles [17,18]. Thus, multichannel stimulation could allow high differential selectivity even between closely located neural elements.…”

“…Also, short turn-on and turn-off times of the field and rapid changes between frequency channels are required for reasonable signaling and driving of network effects. So far, multichannel stimulation has only been demonstrated with two channels in the frequency range of tens to hundreds of kilohertz [17,18]. To increase the number of channels for magnetogenetics, new magnetic nanoparticles need to be developed to respond to magnetic fields in the megahertz range.…”

“…We demonstrate a system with three channels, each separated by a factor of ten in frequency and field strength for the required amplitudefrequency product [21,23] 1). The wide band of frequencies among the channels encompass the range of existing magnetic nanoparticles with good selectivity [17,18] and enable the exploration of novel nanoparticles responding preferably to higher frequencies.…”