Fusion of nanomagnetic and viral tools to interrogate brain-body circuits

摘要 外周器官和大脑之间的信息流越来越被认为是双向的， 外周回路中的活动影响包括情绪、动机和压力在内的高级行为。至 在外周神经元活动和大脑回路之间建立机械联系，我们将培育出一种物种-- 靶向和远程调节外周器官内特定细胞的不可知性框架 大脑在行为过程中。我们的框架将结合制导、调制和对比度特性 具有病毒载体靶向性的磁性纳米材料。 磁性纳米材料最近作为远程应用的弱磁的多功能换能器而出现 离子通道感受到的热、化学或机械刺激。我们将极大地扩展 磁性纳米换能器调色板，可实现对神经元的受体特定远程磁调制(或 其他产电细胞)在自由行为期间在体内的任何位置。此外，我们将利用最近的进展 在腺相关病毒载体中，通过创建一系列融合的 纳米换能器和病毒衣壳。这将允许磁引导和定位混合磁力- 病毒在全身注射后融合到感兴趣的位置，而不考虑模型生物体。 我们将应用我们的框架来阐明连接肠道神经系统和中脑的回路。 结构。最近的研究发现，胃肠功能障碍与社交和情绪障碍之间存在联系，比如 同时也证明了肠道信号向大脑的迷走神经传输。通过应用特定受体 肠道神经元的调制，我们打算检验他们的活动影响中脑通路的假说 管理奖励和动机，可能还有运动行为。 除了支持肠道-大脑回路的研究外，我们的物种不可知框架还可以扩展到 研究任何外周器官和大脑之间的联系，从而打开发展的机会 针对神经和精神疾病的外周器官干预。

Abstract The information flow between the peripheral organs and the brain is increasingly recognized as bidirectional, with activity in peripheral circuits influencing high-level behaviors including mood, motivation, and stress. To establish mechanistic links between activity of peripheral neurons and brain circuits, we will develop a species- agnostic framework for targeting and remote modulation of specific cells within the peripheral organs and the brain during behavior. Our framework will combine the homing, modulation, and contrast properties of synthetic magnetic nanomaterials with the targeting specificity of viral vectors. Magnetic nanomaterials have recently emerged as versatile transducers of remotely applied weak magnetic fields into thermal, chemical, or mechanical stimuli perceived by ion channels. We will dramatically expand the palette of magnetic nanotransducers to enable receptor-specific remote magnetic modulation of neurons (or other electrogenic cells) anywhere in the body during free behavior. Moreover, we will leverage recent advances in adeno-associated viral vectors for targeting specific cells and tissues by creating an array of fusions of nanotransducers and viral capsids. This will allow for magnetic guidance and localization of the hybrid magnetic- viral fusions to the locations of interest following systemic delivery regardless of the model organism. We will apply our framework to elucidate circuits connecting the enteric (gut) nervous system to the midbrain structures. Recent work has drawn links between gastrointestinal dysfunction and social and mood disorders as well as demonstrated vagal transmission of the enteric signals to the brain. By applying receptor-specific modulation to the enteric neurons we intend to test the hypothesis that their activity influences midbrain pathways governing reward and motivation, and possibly motor behaviors. In addition to empowering studies of gut-brain circuits, our species-agnostic framework can be extended to investigate connections between any peripheral organ and the brain thus opening opportunities to develop peripheral organ interventions for neurological and mental conditions.