Remote Modulation of the Peripheral Nervous System

项目摘要 调节支配特定器官的外周神经的活动以及这些器官内的确定的细胞类型 器官将帮助我们理解神经信号和器官功能之间的关系。我们建议 开发和验证非侵入性神经调制在体内周围神经系统中的应用。许多 工具可用于对中枢神经系统中的神经活动进行时间调节，从光激活通道到 设计师受体，但这些不是普遍适用的，特别是在外围。光学方法 需要永久性的植入物，其可能难以固定或甚至在外周组织中造成损伤。在 此外，这些工具仅激活器官的一小部分中的局部神经群。相比之下，设计师 受体和它们的配体可以在更大的区域上靶向神经元，但是具有相对慢的时间过程。 利用无线电波或磁场的神经调制允许远程、快速激活或抑制神经元的活动。 整个器官的活动。 我们最近已经证明，非侵入性无线电波和磁场信号的独特组合， 生物铁蛋白纳米颗粒和生物工程离子通道可用于远程激活和抑制 自由活动动物的CNS神经活动。靶向神经元表达基因编码的纳米颗粒 系于一个修饰的离子通道，瞬时受体电位香草素1，TRPV 1。无线电波或磁场 场自由地穿透组织以加热和/或移动纳米颗粒并激活TRPV 1。修改 TRPV 1允许神经激活或沉默。我们现在将开发和验证用于非侵入性 激活和沉默周围神经使用病毒载体适用于几个物种，我们将 通过调节内分泌胰腺的神经支配来证明它们的效用。具体而言，我们将开发， 验证和表征1）用于远程激活和抑制支配胰腺的神经元的工具， 具有逆行扩散和神经元特异性表达激活或抑制构建体的病毒和2）工具 用于远程激活和抑制特定神经通路（副交感神经、交感神经和感觉神经） 支配胰腺 我们将开发一系列工具，用于远程调制副交感神经，交感神经和感觉神经。 支配器官的周围神经。这些工具将具有广泛的适用性， 可用于研究周围神经在调节器官功能中的生理作用。

Project Summary Modulating the activity of peripheral nerves innervating specific organs and defined cell types within these organs will help us understand the relationship between neural signals and organ function. We propose to develop and validate the use of non-invasive neural modulation in the peripheral nervous system in vivo. Many tools can be used for temporal regulation of neural activity in the CNS, from light activated channels to designer receptors but these are not universally applicable, particularly in the periphery. Optical methods require permanent implants which may be difficult to fix or even cause damage in peripheral tissues. In addition, these tools only activate local neural populations in a small portion of an organ. In contrast, designer receptors and their ligands can target neurons across a larger area but have a relatively slow time course. Neural modulation with radiowaves or magnetic fields allows remote, rapid activation or inhibition of neural activity across an entire organ. We have recently shown that a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels can be used to remotely activate and inhibit CNS neural activity in freely moving animals. Targeted neurons express genetically encoded nanoparticles tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields freely penetrate tissue to heat and/or move the nanoparticle and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will now develop and validate tools for non-invasive activation and silencing of peripheral nerves using viral vectors applicable to several species and we will demonstrate their utility by modulating innervation of the endocrine pancreas. Specifically, we will develop, validate and characterize 1) tools for remote activation and inhibition of neurons innervating the pancreas using viruses with retrograde spread and neuron-specific expression of activating or inhibitory constructs and 2) tools for remote activation and inhibition of specific neural pathways (parasympathetic, sympathetic and sensory) innervating the pancreas. We will develop a range of tools for remote modulation of parasympathetic, sympathetic and sensory peripheral nerves innervating an organ. These tools will be broadly applicable and extend the methods available to investigate the physiological roles of peripheral nerves in regulating organ function.