Remote regulation of neural activity

 描述(申请人提供)：神经科学的一个基本目标是了解复杂生物体中确定的神经群体的功能(S)。我们建议开发和验证一种非侵入性调节体内神经活动的技术。在开发神经活动的时间调节工具方面取得了巨大的进展。这些技术，从光激活通道到设计受体，能够在体内调节特定的神经群体，以检查它们在许多生理功能中的作用。但目前的技术有其局限性。光学方法需要永久植入，并且只激活局部神经种群，而设计者受体及其特定配体的时间过程要慢得多。理想情况下，工具应该能够以快速的时间分辨率远程调节处于多个发展阶段的局部或分散的神经群体中的神经活动。我们通过使用非侵入性无线电波和磁场信号、生物铁蛋白纳米颗粒和生物工程离子通道的独特组合来应对这一挑战，以非侵入性方式调节自由运动动物的神经活动。射频或磁场远程调制神经元，表达在修饰的铁蛋白外壳中形成的纳米颗粒。这些细胞被连接到一个修饰的离子通道，瞬时受体电位香草素1，TRPV1。无线电波或磁场穿透组织，分别加热或移动纳米颗粒，并激活TRPV1。TRPV1的修饰允许神经激活或沉默。我们将开发和验证使用适用于几个物种的病毒载体的非侵入性激活和沉默神经种群的工具，并展示它们在调节复杂行为方面的有效性。具体地说，我们将1)表征体外神经元群体对射频和磁场操纵的电生理反应，2)检测体内下丘脑神经元对射频或磁场调制的反应，并将它们与光遗传调制进行比较，以及3)确定与设计药物(DREADD)调制专门激活的设计者受体相比，调制分散在皮质层(小脑浦肯野细胞)的神经群体在体内的效果。利用生物工程纳米颗粒传递电磁信号，我们将通过开发开发一种独特的技术，用于定向、非侵入性地操纵神经活动，适用于局部或分散的细胞。 我们的技术将是对现有工具的宝贵补充，以研究神经群体的生理作用。

 DESCRIPTION (provided by applicant): A fundamental goal of neuroscience is to understand the function(s) of defined neural populations in a complex organism. We propose to develop and validate a technology for non- invasive modulation of neural activity in vivo. There has been huge progress in developing tools for temporal regulation of neural activity. These techniques, from light activated channels to designer receptors, enable modulation of defined neural populations in vivo to examine their roles in many physiological functions. But current technologies have their limitations. Optical methods require permanent implants and activate only local neural populations while designer receptors and their specific ligands have a significantly slower time course. Ideally, tools would be capable of remote modulation of neural activity in local or dispersed neural populations at multiple stages of development with rapid temporal resolution. We address this challenge by using a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels for non- invasive modulation of neural activity in freely moving animals. Radiofrequency or magnetic fields remotely modulate neurons that express nanoparticles formed in a modified ferritin shell. These are tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields penetrate tissue to heat or move the nanoparticle respectively and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will develop and validate tools for non-invasive activation and silencing of neural populations using viral vectors applicable to several species and demonstrate their utility in regulating complex behaviors. Specifically, we will 1) characterize the electrophysiological responses to RF and magnetic manipulation of neural populations in vitro, 2) examine the responses to RF or magnetic field modulation of hypothalamic neurons in vivo and compare them to optogenetic modulation and 3) determine the effects of modulating a neural population that is dispersed through a cortical lamina, the cerebellar Purkinje cells, in vivo in comparison to designer receptors exclusively activated by designer drugs (DREADD) modulation. Using bioengineered nanoparticles to transduce electromagnetic signals, we will develop a unique technology for targeted, non-invasive manipulation of neural activity that is applicable to local or dispersed cells through development. Our technology will be a valuable addition to the available tools to investigate the physiological roles of neural populations.