Fast Multichannel Magneto-thermal Genetics

快速多通道磁热遗传学

• 批准号: 10401691
• 负责人: Jacob T. Robinson
• 金额: $ 214.55万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401691
• 关键词: Animal Behavior; Animal Model; Animals; Area; Behavior; Brain; Caenorhabditis elegans; Cell Culture Techniques; Cells; Contralateral; Cues; Development; Drosophila melanogaster; Environment; Etiology; Formulation; Frequencies; Genetic; Goals; Heating; Housing; Implant; Injectable; Injections; Ion Channel; Magnetic nanoparticles; Magnetism; Mammalian Cell; Measures; Methods; Motor Cortex; Mus; Neurobiology; Neurons; Population; Reaction Time; Research; Research Personnel; Response Latencies; Rotation; Sensory; Social Interaction; Stimulus; TRPA channel; Techniques; Technology; Testing; Thermoreceptors; Tissues; Virus; Work; base; brain behavior; cell type; experimental study; field study; fly; implantable device; improved; in vivo; innovation; magnetic field; minimally invasive; nanoparticle; nervous system disorder; neural circuit; neural stimulation; neuroregulation; neurotechnology; optogenetics; relating to nervous system; remote control; temporal measurement; tool; wearable device; wireless

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.

抽象的 精确定时激活基因靶向细胞是研究神经回路的有力工具。神经元调节（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。最近的工作已经产生了许多用于基因靶向神经调节的工具；然而，理想的技术应该是： 1）无线——实现不受限制的动物行为和社会互动。 2) 可注射——最大限度地减少组织损伤并简化与植入相关的实施。 3) 快速——（亚秒级响应时间）使神经刺激与行为或感觉队列同步。 4) 多路复用——以便不同的大脑区域、细胞类型或动物可以在同一区域内进行调节。 具有这些功能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，当动物彼此及其环境相互作用时，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。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。 为了创造这种类型的神经调节技术，我们将开发第一个快速磁热遗传学。该技术依靠交变磁场来加热纳米颗粒，从而激活基因靶向细胞中表达的温度感受器。虽然类似的磁热方法最近已在小鼠和秀丽隐杆线虫中得到证实，但响应延迟仍然超过 10 秒，使得神经调节与行为或感觉线索不可能精确同步。我们建议使用高度敏感的速率依赖性温度感受器和优化的纳米粒子，以亚秒级延迟实现对基因靶向细胞的磁控制。我们还建议通过调整磁性纳米粒子的成分，使磁性纳米粒子对特定磁场振幅和频率具有更大的选择性。这些优化将使独立神经回路或邻近动物的多通道远程刺激成为可能。 我们的工具将使磁遗传学更接近光遗传学可能的时间分辨率和多重刺激，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。