Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor

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.Abstract现有的神经调控技术, 如光遗传学和深部脑刺激, 正在改变基础研究和临床转化神经科学。然而这两种调控方式都是损伤性的, 因为需要在大脑里植入光纤或者金属电极。在这个研究中, 我们新发明了一种非损伤性的神经调控方法, 称之为“磁遗传学”。这个方法结合基因打靶和磁场刺激, 将这个进化上高度保守的外源性的磁感应受体, 一种铁硫蛋白 (Isca1), 导入到大脑特定的区域, 使其在特定的神经元中表达, 然后通过外部磁场刺激, 激活大脑特定的区域。在体外培养的HEK-293细胞和海马神经元中表达该磁感应受体, 施加外部磁场, 能激活细胞, 导致细胞膜去极化和钙离子内流。这种钙离子内流可以由超灵敏荧光钙指示剂GCaMP6s检测出来, 当细胞内钙离子浓度升高时, GCaMP6s的荧光强度会升高。此外, 磁场控制神经元的活动可能依赖于磁场的方向以及磁场的打开和关闭, 对于不同方向的磁场刺激, 以及磁场的开关, 神经元有不同的反应模式。全细胞膜片钳记录的神经元的电信号显示外界磁场可以使表达磁感应受体的神经元去极化, 从而引起动作电位。通过肌肉细胞特定的启动子myo-3将这个受体导入线虫的肌肉细胞内, 外加磁场可以触发线虫肌肉收缩 ; 通过神经细胞的特定启动子mec-4将磁感应受体导入应力感受神经元, 外界磁场的刺激可诱发线虫后退的行为。磁遗传学和光遗传学相比, 明显的优势是非损伤性, 高穿透深度, 长久持续刺激, 无空间限制性, 空间均匀性和相对安全性。正如光遗传学通过了十年之久的改之后所取得的进展一样, 磁遗传学开辟了一个全新的神经调控领域, 经过持续的发展和成熟, 将有广泛的应用前景, 并将极大地推动基础研究, 转化神经科学以及其它生物科学的发展。我们预见一个磁遗传学时代的来临。