Center for Extreme Bionics, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Harvard-MIT Division of Health Sciences and Technology (HST), Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America.
J Neural Eng. 2019 Aug 21;16(5):054002. doi: 10.1088/1741-2552/ab1e22.
Over the last two decades, optical control of neuronal activity in the central nervous system has seen rapid development, demonstrating the utility of optogenetics as both an experimental and therapeutic tool. Conversely, applications of optogenetics in the peripheral nervous system have been relatively constrained by the challenges of temporally variable opsin expression, light penetration and immune attack of non-native opsins. Whilst opsin expression can be increased significantly through high-concentration viral induction, subsequent attack by the immune system causes temporal decay and high variability in electrophysiological response.
In this study, we present a method to circumvent the aforementioned challenges by locally supplementing all-trans-retinal (ATR) (via a slow release pellet) to increase tissue photosensitivity in transgenic mice expressing channelrhodopsin 2 (ChR2) in nerves.
In mice supplemented with ATR, we demonstrate enhanced electrophysiological activation and fatigue tolerance in response to optical stimulation for six weeks.
Local supplementation of ATR enables improved optogenetic stimulation efficacy in peripheral nerves. This method enables greater exploration of neurophysiology and development of clinically-viable optogenetic treatments in the peripheral nervous system.
在过去的二十年中，中枢神经系统中神经元活动的光控技术得到了快速发展，这证明了光遗传学作为一种实验和治疗工具的实用性。相反，由于变构蛋白表达的时变、光穿透和非天然变构蛋白的免疫攻击等挑战，光遗传学在周围神经系统中的应用相对受到限制。虽然通过高浓度病毒诱导可以显著增加变构蛋白的表达，但随后免疫系统的攻击会导致电生理反应的时间衰减和高度可变性。
在本研究中，我们提出了一种方法来规避上述挑战，通过局部补充全反式视黄醛（ATR）（通过缓慢释放颗粒）来增加在神经中表达通道视紫红质 2（ChR2）的转基因小鼠的组织光敏感性。
在接受 ATR 补充的小鼠中，我们证明了在光学刺激下，电生理激活和疲劳耐受性增强，持续了六周。
ATR 的局部补充使外周神经中的光遗传学刺激效果得到改善。该方法能够更深入地探索神经生理学，并开发外周神经系统中可行的临床光遗传学治疗方法。
