Abstract
Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non-invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on-response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic Caenorhabditis elegans expressing this magnetoreceptor in myo-3-specific muscle cells or mec-4-specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade-long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming.
Highlights
The complex neural microcircuits are the essential building blocks of how the brain works, but they are entangled with interdependent different cell types, interconnected wiringSci
The noninvasive activation of neuronal activity was executed through an iron-sulfur assembly protein, iron-sulfur cluster assembly protein 1 (Isca1) [18,19,20]. We speculate that this iron-containing magnetoreceptor might form as an iron-sulfur cluster that could bind to cellular plasma membrane through either cytoskeletons or filaments [18, 21, 22]. We found that this magnetoreceptor could evoke membrane depolarization and action potentials, generate calcium influx, and trigger neuronal activity in both human embryonic kidney (HEK)-293 and cultured primary hippocampal neurons when activated by a remote magnetic field
All C. elegans strains were grown and maintained on nematode growth media (NGM) agar plates cultured at 20 °C
Summary
The complex neural microcircuits are the essential building blocks of how the brain works, but they are entangled with interdependent different cell types, interconnected wiringSci. Even though the most popular optogenetics could spatiotemporally activate or deactivate neural activity with a millisecond precision [12,13,14] and has rapidly transformed neuroscience, the side effects from opsin expression patterns, laser-induced heating, abnormal ions distribution caused by overexpressed pumps or channels, and/or undesired network homeostasis can make experimental interpretation very difficult [15] Both optogenetics and deep-brain stimulation have been used to invasively manipulate the neuronal activity of a specific subregion in the intact mammalian brain through a permanently implanted electric wire or optical fiber during the chronic surgery [9, 16, 17]. There has been a high demand on a new generation of exclusively noninvasive neuroperturbation and neuromodulation toolboxes for the whole brain at both microcircuit and macrocircuit levels
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