Fast Multichannel Magneto-thermal Genetics

摘要 精确定时激活基因靶向细胞是研究神经回路的有力工具。神经调节(激活或抑制选定的神经元)使我们能够研究神经活动如何导致动物行为的变化。最近的工作导致了许多针对基因定向神经调节的工具；然而，理想的技术应该是：1)无线--使动物的行为和社会互动不受限制。2)可注射-将组织损伤降至最低，并简化与植入相关的实施。3)快速(亚秒响应时间)，使神经刺激与行为或感觉队列同步。4)多路传输--因此不同的大脑区域、细胞类型或动物可以在同一个竞技场中进行调节。具有这些能力的技术将成为发现神经回路活动和行为之间因果关系的强大工具。例如，研究人员将能够操纵分布在整个大脑中的整个神经回路的活动，因为动物之间和他们的环境相互作用。通过这些实验，研究人员将能够发现如何选择神经元参与特定行为。为了创造这种神经调节技术，我们将开发第一个快速磁热遗传学。这项技术依赖于交变磁场来加热纳米颗粒，这些纳米颗粒激活在基因靶向细胞中表达的温度感受器。虽然最近在小鼠和线虫身上也展示了类似的磁热方法，但反应潜伏期一直保持在10秒以上，这使得神经调节与行为或感觉线索精确同步是不可能的。我们建议使用高度敏感的速率依赖的温度感受器和优化的纳米颗粒来实现对亚秒潜伏期的基因靶细胞的磁性控制。我们还建议通过调整磁性纳米颗粒的组成，使其对特定磁场的幅度和频率具有更强的选择性。这些优化将允许对独立的神经回路或位于附近的动物进行多通道远程刺激。我们的工具将使磁遗传学更接近光遗传学可能实现的时间分辨率和多路刺激，同时保持只有通过磁控制才能实现的最小侵入性和深层组织刺激。

Abstract Precisely timed activation of genetically targeted cells is a powerful tool for studying neural circuits. Neuronal modulation (activating or inhibiting select neurons) allows us to investigate how neural activity causes changes in animal behavior. Recent work has led to many tools for genetically targeted neuromodulation; however, the ideal technology should be: 1) Wireless – to enable unrestricted animal behavior and social interactions. 2) Injectable – to minimize tissue damage and ease implementation associated with implants. 3) Fast – (sub-second response times) to synchronize neural stimulation with behaviors or sensory queues. 4) Multiplexed – so that different brain areas, cell types, or animals can be modulated within the same arena. A technology with these capabilities will be a powerful tool for discovering causal relationships between neural circuit activity and behavior. For example, researchers will be able to manipulate the activity of entire neural circuits distributed throughout the brain as animals interact with one another and their environment. Through these experiments, researchers will be able to discover how to select neurons to participate in specific behaviors. To create this type of neuromodulation technology, we will develop the first fast magnetothermal genetics. This technique relies on alternating magnetic fields to heat nanoparticles that activate thermoreceptors expressed in genetically targeted cells. While similar magnetothermal approaches have been recently demonstrated in mice and C. elegans, response latencies have remained in excess of 10 seconds making it impossible to precisely synchronize neural modulation with behaviors or sensory cues. We propose to use highly sensitive rate-dependent thermoreceptors and optimized nanoparticles to achieve magnetic control of genetically targeted cells with sub-second latency. We also propose to make magnetic nanoparticles significantly more selective to specific magnetic field amplitudes and frequencies by tuning their composition. These optimizations will enable multichannel remote stimulation of independent neural circuits or animals located in close proximity. Our tools will bring magnetogenetics closer to the temporal resolution and multiplexed stimulation possible with optogenetics while maintaining the minimal invasiveness and deep-tissue stimulation only possible by magnetic control.