School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China.
BMC Biol. 2021 Nov 24;19(1):252. doi: 10.1186/s12915-021-01187-x.
Although electrical stimulation of the peripheral and central nervous systems has attracted much attention owing to its potential therapeutic effects on neuropsychiatric diseases, its non-cell-type-specific activation characteristics may hinder its wide clinical application. Unlike electrical methodologies, optogenetics has more recently been applied as a cell-specific approach for precise modulation of neural functions in vivo, for instance on the vagus nerve. The commonly used implantable optical waveguides are silica optical fibers, which for brain optogenetic stimulation (BOS) are usually fixed on the skull bone. However, due to the huge mismatch of mechanical properties between the stiff optical implants and deformable vagal tissues, vagus nerve optogenetic stimulation (VNOS) in free-behaving animals continues to be a great challenge.
To resolve this issue, we developed a simplified method for the fabrication of flexible and stretchable polymer optical fibers (POFs), which show significantly improved characteristics for in vivo optogenetic applications, specifically a low Young's modulus, high stretchability, improved biocompatibility, and long-term stability. We implanted the POFs into the primary motor cortex of C57 mice after the expression of CaMKIIα-ChR2-mCherry detected frequency-dependent neuronal activity and the behavioral changes during light delivery. The viability of POFs as implantable waveguides for VNOS was verified by the increased firing rate of the fast-spiking GABAergic interneurons recorded in the left vagus nerve of VGAT-ChR2 transgenic mice. Furthermore, VNOS was carried out in free-moving rodents via chronically implanted POFs, and an inhibitory influence on the cardiac system and an anxiolytic effect on behaviors was shown.
Our results demonstrate the feasibility and advantages of the use of POFs in chronic optogenetic modulations in both of the central and peripheral nervous systems, providing new information for the development of novel therapeutic strategies for the treatment of neuropsychiatric disorders.
尽管外周和中枢神经系统的电刺激因其对神经精神疾病的潜在治疗效果而受到广泛关注，但由于其非细胞类型特异性激活特性，可能会阻碍其广泛的临床应用。与电方法不同，光遗传学最近已被用作一种细胞特异性方法，用于在体内精确调节神经功能，例如迷走神经。常用的可植入光学波导是二氧化硅光纤，对于脑光遗传学刺激（BOS），通常固定在颅骨上。然而，由于刚性光学植入物和可变形迷走组织之间的机械性能差异很大，在自由行为动物中进行迷走神经光遗传学刺激（VNOS）仍然是一个巨大的挑战。
为了解决这个问题，我们开发了一种制造柔性和可拉伸聚合物光纤（POF）的简化方法，该方法显示出了显著改善的体内光遗传学应用特性，特别是低杨氏模量、高拉伸性、改善的生物相容性和长期稳定性。我们在 C57 小鼠的初级运动皮层中表达 CaMKIIα-ChR2-mCherry 后，将 POF 植入其中，检测到光传递过程中神经元活动和行为变化的频率依赖性。通过记录在 VGAT-ChR2 转基因小鼠左侧迷走神经中快速放电 GABA 能中间神经元的放电率，证明了 POF 作为 VNOS 可植入波导的可行性。此外，通过慢性植入的 POF 在自由活动的啮齿动物中进行了 VNOS，并显示出对心脏系统的抑制作用和对行为的抗焦虑作用。
我们的结果证明了 POF 在中枢和外周神经系统的慢性光遗传学调节中的可行性和优势，为开发用于治疗神经精神疾病的新型治疗策略提供了新的信息。
