Multi-Site Non-Invasive Magnetothermal Excitation and Inhibition of Deep Brain Structures

摘要 该项目旨在开发一种无线、微创双向脑深部刺激技术。 基于磁性纳米颗粒的远程加热。可靠地调节特定神经元的活动 种群对于建立神经放电模式和观察到的行为之间的因果联系至关重要。 电刺激及其最新的非侵入性替代品，超声波和电磁感应， 不区分单元格类型，空间分辨率有限。遗传方法，如 DREADD和光遗传学使特定细胞中的神经兴奋和抑制具有精确度 人口。然而，它们需要长期的留置硬件(限制临床翻译)或缺乏时间 决议。在这个项目中，我们建议对一种基于纳米颗粒的技术进行评估，该技术可以访问深海 大脑区域，兴奋和抑制神经元，并在初始注射后完全无线。Anikeeva(麻省理工学院)和 Pralle(纽约州立大学水牛分校)的研究小组最近发现，磁性纳米颗粒(MNPs)在人体内的散热 交变磁场可触发热敏性辣椒素受体TRPV1和热敏性 氯通道ANO1(ANO1)。反过来，这些又可以使神经元去极化或沉默，而我们 在体外和体内都有初步的效果证据。最后，Anikeeva小组取得了进展 在纳米材料化学中，能够实现多路复用：多种MNP类型的独立加热(意味着 控制多个相邻神经群)使用具有不同幅度和频率的AMF。我们的 目标是将这些技术结合到一个“磁热工具箱”中，并展示其 通过操纵一个特征良好的中脑奖励回路来塑造动物行为的能力。我们会改进的 ANO1抑制技术并演示了对小鼠位置厌恶的控制(目标1)，然后将其合并 在磁复用背景下使用TRPV1促进的励磁技术来显示双向控制 地点厌恶/偏好(目标2)。从这个概念证明中，Aim 3试图证明该工具包可以 在更大的物种(老鼠)中，也控制了更复杂的行为(赌博/概率奖励学习)。我们会 通过纳米工程专业知识的紧密结合来实施该项目(Anikeeva， Pralle)，靶向神经调节(Anikeeva，Pralle)，通过中脑调节进行行为操纵 (Widge)和临床精神病学脑深部刺激(Widge)。

Abstract This project seeks to develop a wireless, minimally invasive bi-directional deep brain stimulation technology based on remote heating of magnetic nanoparticles. Reliably modulating the activity of specific neuronal populations is essential to establishing causal links between neural firing patterns and observed behaviors. Electrical stimulation, as well as its recent non-invasive alternatives, ultrasound and electromagnetic induction, do not discriminate between cell types and have limited spatial resolution. Genetic approaches such as DREADDs and optogenetics enable neural excitation and inhibition with exquisite precision in specific cell populations. However, they require long-term indwelling hardware (limiting clinical translation) or lack temporal resolution. In this project, we propose to evaluate a nanoparticle-based technology that can access the deep brain regions, excite and inhibit neurons, and be fully wireless after initial injection. The Anikeeva (MIT) and Pralle (SUNY Buffalo) groups have recently shown that heat dissipation by magnetic nanoparticles (MNPs) in alternating magnetic fields (AMFs) can trigger heat-sensitive capsaicin receptor TRPV1 and heat-sensitive chloride channel anoctamine 1 (ANO1), respectively. These, in turn, can depolarize or silence neurons, and we have preliminary evidence for effects both in vitro and in vivo. Finally, the Anikeeva group has made advances in nanomaterials chemistry that enables multiplexing: independent heating of multiple MNP types (implying control of multiple neighboring neural populations) using AMF with distinct amplitudes and frequencies. Our objective is to combine these technologies into a "magnetothermal toolbox" and demonstrate its ability to shape animal behavior, by manipulating a well-characterized midbrain reward circuit. We will refine the ANO1 inhibitory technology and demonstrate control of place aversion in mice (Aim 1), then merge this technology with TRPV1-facilitated excitation in context of magnetic multiplexing to show bi-directional control of place aversion/preference (Aim 2). From this proof of concept, Aim 3 seeks to demonstrate that the toolkit can also control a more complex behavior (gambling/ probabilistic reward learning) in a larger species (rat). We will carry out this project through a tightly integrated combination of expertise in nanoscale engineering (Anikeeva, Pralle), targeted neural modulation (Anikeeva, Pralle), behavior manipulation through midbrain modulation (Widge) and clinical psychiatric deep brain stimulation (Widge).