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、微创双向脑深部电刺激技术 基于磁性纳米粒子的远程加热。可靠地调节特定神经元的活性 种群对于在神经放电模式和观察到的行为之间建立因果联系至关重要。 电刺激，以及最近的非侵入性替代品，超声波和电磁感应， 不能区分细胞类型并且具有有限的空间分辨率。遗传学方法，如 DREADDs和光遗传学能够在特定细胞中精确地实现神经兴奋和抑制 人口数量。然而，它们需要长期留置硬件（限制临床转化）或缺乏暂时性的 分辨率在这个项目中，我们建议评估一种基于纳米颗粒的技术， 大脑区域，兴奋和抑制神经元，并在初始注射后完全无线。Anikeeva（MIT）和 Pralle（SUNY布法罗）小组最近表明，在热交换器中，磁性纳米颗粒（MNP）的散热作用是非常重要的。 交变磁场（AMF）可以触发热敏辣椒素受体TRPV 1和热敏 氯化物通道anoctamine 1（ANO 1）。反过来，这些可以使神经元去兴奋或沉默， 在体外和体内都有初步的证据。最后，Anikeeva集团取得了进展， 在纳米材料化学，使多路复用：独立加热多种MNP类型（意味着 多个相邻神经群体的控制）使用具有不同幅度和频率的AMF。我们 目标是将这些技术联合收割机组合成一个“磁热工具箱”，并展示其 通过操纵一个特征鲜明的中脑奖励回路来塑造动物行为的能力。我们将完善 ANO 1抑制技术和证明小鼠位置厌恶控制（目的1），然后将此合并 在磁多路复用的背景下具有TRPV 1促进的激发的技术，以显示对 位置厌恶/偏好（目标2）。通过这个概念验证，目标3试图证明该工具包可以 还控制更大物种（大鼠）中更复杂的行为（赌博/概率奖励学习）。我们将 通过纳米级工程专业知识的紧密集成组合来实施该项目（Anikeeva， Pralle）、靶向神经调节（Anikeeva、Pralle）、通过中脑调节进行行为操纵 （Widge）和临床精神病脑深部电刺激（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).