Magnetogenetics Inspired by Animal Magnetoreception: ΔTRPV4MagR as a Novel Magnetogenetic Actuator Enabling Remote Neuromodulation of Brain Circuits

The discovery of a novel magnetic actuator is critical for the application of magnetogenetic technique. However, whether MagR can perceive magnetic fields is ambiguous in previous studies that evoked great interest and debate. Here, the fusion protein ΔTRPV4MagR is constructed by genetically linking MagR to the C-terminus of truncated TRPV4, and the magnetic perception capacity of MagR is read out by TRPV4 cation channel characteristics in vitro and in vivo. Upon magnetic stimulation, ΔTRPV4MagR expressing HEK293T cells exhibited calcium influx in a strength-dependent manner examined by the Fluo-4 experiment. While under 40 mT, 0.1 Hz magnetic stimulation, ΔTRPV4MagR induced calcium influx was more potent than Magneto 2.0 (ΔTRPV4Ferritin). Interestingly, the MagR of pigeon (cMagR) or human origin has superior magnetic sensitivity to that of drosophila origin (dMagR). Moreover, for the freely moving mice, ΔTRPV4cMagR expression successfully raises the intracellular calcium level of brain neurons and operates dopamine release from VTA dopaminergic neurons under magnetic stimulation. Remarkably, the effectiveness of ΔTRPV4cMagR is further validated by magnetic control of mice rotating around the body-axis and freezing-of-gait. This work not only witnesses the magnetoperceptive capacity of MagR, but also provides a promising effective means to manipulate specific neuron populations in brain circuits temporally and remotely.