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， 周边回路的活动影响高水平的行为，包括情绪、动机和压力。到 建立周围神经元活动和大脑回路之间的机械联系，我们将发展出一个物种- 用于靶向和远程调节外周器官内的特定细胞的不可知框架， 大脑在行为我们的框架将结合联合收割机的归巢，调制，和合成的对比度属性， 具有病毒载体靶向性的磁性纳米材料。 磁性纳米材料最近成为远程应用弱磁性的多功能换能器 场转化为离子通道感知的热、化学或机械刺激。我们将大幅扩大 磁纳米换能器的调色板，以实现神经元的受体特异性远程磁调制（或 其他产电细胞）在自由行为期间身体的任何地方。此外，我们将利用最近的进展， 在腺相关病毒载体中，通过产生一系列融合物， 纳米转换器和病毒衣壳。这将允许磁引导和混合磁定位- 无论模型生物体如何，在全身递送后病毒融合到感兴趣的位置。 我们将应用我们的框架来阐明连接肠神经系统和中脑的回路 结构.最近的研究表明，胃肠功能障碍与社交和情绪障碍之间存在联系， 并证明肠信号向大脑的迷走神经传递。通过应用受体特异性 调节肠神经元，我们打算测试的假设，他们的活动影响中脑途径 控制着奖励和动机，可能还有运动行为。 除了赋予肠脑回路的研究权力，我们的物种不可知论框架可以扩展到 研究任何外周器官和大脑之间的联系，从而为发展创造机会。 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.