Genetically targeted magnetic control of the nervous system

Abstract

Optogenetic and chemogenetic actuators are critical for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or slow on/off kinetics. We have overcome these disadvantages by synthesizing a single component, magnetically sensitive actuator, “Magneto,” comprised of the cation channel, TRPV4, fused to the paramagnetic protein, ferritin. We validate non-invasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together, our results present Magneto as a novel actuator capable of remotely controlling circuits associated with complex animal behaviors.

Thermal Transients Excite Neurons through Universal Intramembrane Mechanoelectrical Effects

“…Also, the identified mechanoelectrical effects are dominant in the short time scales considered here, but in conjunction with parallel thermal effects like changes in the Q 10 factor [47], probably play a significant role under a wide array of thermal modulation scenarios [48]. Related insights may also help guide our understanding of other emerging neurophysical modalities like magnetogenetic stimulation (whose biophysics is still poorly understood [49,50]). For example, we note that membrane mechanoelectrical effects involving dimensional changes were suggested in other contexts involving changes in intramembranal forces, including action potential-related intramembrane thickness variations [51][52][53] and ultrasoundinduced formation of intramembrane cavities (or "bilayer sonophores" [54]).…”

Acute and Chronic Neural Stimulation via Mechano-Sensitive Ion Channels

“…Our argument is hence similar to thermo/magneto-genetics where it is expected that the applied heat or mechanical stimuli might also activate intrinsic heat/mechano-sensitive ion channels. [170][171][172][173] Although there is a possibility that other mechano-sensitive ion channels might be activated by magnetic forceinduced stretching of lipid membrane, we showed that the contribution by N-type Ca 2+ channels was the largest (Fig. 5g).…”

“…Next, we monitored the expression of TRPV4 which is the only type of mechano-sensitive ion channel other than N-type calcium channel that has been reported for neural stimulation. 173 However, chronic stimulation did not affect the expression of TRPV4 (Appendix B Fig. 2a-b).…”

“…(c) The only 2 types of mechano-sensitive ion channels that have been reported for use in magnetic neural stimulation are N-type calcium channels 58 and TRPV4. 313 Currently, the peptide domains responsible for sensing mechanical stimuli are unclear. In addition, the threshold and mechanism for activating different mechano-sensitive ion channels are not known.…”

Identification of medaka magnetoreceptor and cryptochromes

“…For example, in neuroscience, magnetogenetics was recently reported as a promising noninvasive technique to control gene expression and cellular activity in vivo (Etoc et al, 2013;Etoc et al, 2015;Long et al, 2015;Stanley et al, 2015;Stanley et al, 2016;Wheeler et al, 2016). It shows many advantages over the currently widely used techniques such as deep-brain stimulation and optogenetics (Wichmann and Delong, 2006;Zhang et al, 2011), which require surgical implantation of a wire electrode or optical fiber (Kringelbach et al, 2007;Häusser, 2014).…”