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.

Keywords

Abstract

現(xiàn)有的神經調控技術, 如光遺傳學和深部腦刺激, 正在改變基礎研究和臨床轉化神經科學。然而這兩種調控方式都是損傷性的, 因為需要在大腦里植入光纖或者金屬電極。在這個研究中, 我們新發(fā)明了一種非損傷性的神經調控方法, 稱之為“磁遺傳學”。這個方法結合基因打靶和磁場刺激, 將這個進化上高度保守的外源性的磁感應受體, 一種鐵硫蛋白 (Isca1), 導入到大腦特定的區(qū)域, 使其在特定的神經元中表達, 然后通過外部磁場刺激, 激活大腦特定的區(qū)域。在體外培養(yǎng)的HEK-293細胞和海馬神經元中表達該磁感應受體, 施加外部磁場, 能激活細胞, 導致細胞膜去極化和鈣離子內流。這種鈣離子內流可以由超靈敏熒光鈣指示劑GCaMP6s檢測出來, 當細胞內鈣離子濃度升高時, GCaMP6s的熒光強度會升高。此外, 磁場控制神經元的活動可能依賴于磁場的方向以及磁場的打開和關閉, 對于不同方向的磁場刺激, 以及磁場的開關, 神經元有不同的反應模式。全細胞膜片鉗記錄的神經元的電信號顯示外界磁場可以使表達磁感應受體的神經元去極化, 從而引起動作電位。通過肌肉細胞特定的啟動子myo-3將這個受體導入線蟲的肌肉細胞內, 外加磁場可以觸發(fā)線蟲肌肉收縮 ; 通過神經細胞的特定啟動子mec-4將磁感應受體導入應力感受神經元, 外界磁場的刺激可誘發(fā)線蟲后退的行為。磁遺傳學和光遺傳學相比, 明顯的優(yōu)勢是非損傷性, 高穿透深度, 長久持續(xù)刺激, 無空間限制性, 空間均勻性和相對安全性。正如光遺傳學通過了十年之久的改之后所取得的進展一樣, 磁遺傳學開辟了一個全新的神經調控領域, 經過持續(xù)的發(fā)展和成熟, 將有廣泛的應用前景, 并將極大地推動基礎研究, 轉化神經科學以及其它生物科學的發(fā)展。我們預見一個磁遺傳學時代的來臨。

Xiaoyang Long and Jing Ye contributed equally to this work.

The online version of this article (doi:10.1007/s11434-015-0902-0) contains supplementary material, which is available to authorized users.