Project 1

项目1摘要 在这里，我们实施了一种技术驱动的方法来识别和控制潜在的药物电路动力学- 在带有回报和风险的背景下，调节社会和非社会行为。我们应用技术 代表着药物滥用研究机会的主要结合(光脑成像或OEG，框架- 投射独立纤维光度法(FIP)和清晰度优化的光片显微镜(COLM) 这不仅允许观察和控制遗传定义的电路，而且允许观察和控制多个电路元件 同时和独立--在药物改变状态下的行为之前、期间和之后。在目标1中，我们 从清醒的啮齿动物最广泛的(全脑)范围开始，找出公正的关键角色和原则 时尚，同时保持电路元件的特异性，以观察和控制活动。从技术上讲， 目标1实验将包括针对特定电路的光遗传驱动的精确脉冲模式 预测，以及基于磁共振成像的快速和定量的全脑活动评估 模式。这些最初的不偏不倚的全球评估将有力地提供信息，并更多地关注空间限制 目标2和目标3中的研究，解决了剧烈变化状态的基本特征。在目标2中，我们在 更高的空间和时间分辨率，下一步是详细阐明因果电路 在剧烈的药物改变状态下的动态。针对目标1号相同的药物和行为状况，现在 在个体-动物水平上定量地指导要使用 人口和预测-FIP的特定记录能力，我们在人口和预测的模式中发挥作用 测试对行为的因果影响的活动。在Aim 3中，我们利用最高分辨率的新 方法，尽管如此，仍保持着广阔的前景。我们现在能够想象(使用OEG以及 共振扫描双光子显微镜)大量的大脑和量化的高速动态活动 特定于细胞类型的模式，接近单个细胞的分辨率，同时保持类似于地图的全脑范围 视角、行为期间和吸毒期间的滥用。干预性因果关系检验将是 直接受到这些观察的指导。如下所述，我们已经观察到高度特异的大脑皮层 对亚麻醉剂量氯胺酮的反应活动模式，这里将扩大到同一药物 以及与目标1和2有关的行为状况。这种对不同神经的精确观察和控制 电路路径与项目2-4中描述的研究计划紧密交织在一起， 技术和培训核心。总而言之，项目1中的这些实验将测试多功能、强大的新 NIDA中心和更广泛的药物滥用社区使用的电路动力学工具，并将 也应用这些工具来加深我们对急性或长期改变的药物改变状态的理解，以及 大脑本身就是一个动力系统。

Project 1 Summary Here we implement a technology-driven approach to identify and control circuit dynamics underlying drug- modulated social and nonsocial behaviors, in contexts carrying reward and risk. We apply technology representing a major alignment of opportunity for drug abuse research (optoencephalography or OEG, frame- projected independent-fiber photometry or FIP, and CLARITY-optimized lightsheet microscopy or COLM) which allow not only observation and control of genetically-defined circuitry, but multiple circuit elements simultaneously and independently-- before, during and after behaviors in the drug-altered state. In Aim 1, we begin at the broadest (brainwide) scale in awake rodents, to identify key players and principles in unbiased fashion, while maintaining circuit element-specificity for observation and control of activity. Technologically, Aim 1 experiments will include optogenetically-driven precise pulse patterns targeted to specific circuits and projections, as well as rapid and quantitative COLM- or ofMRI- based assessment of brainwide activity patterns. These initial unbiased global assessments will powerfully inform and focus more spatially-restricted investigations in Aims 2 and 3 that resolve essential features of acutely altered states. In Aim 2 we operate at much higher spatial and temporal resolution, the next step toward detailed elucidation of causal circuit dynamics in the acutely drug-altered state. For the same drug and behavioral conditions in Aim 1, now quantitatively guided at the individual-animal level in terms of neuronal activity levels to be targeted using the population and projection-specific recording capability of FIP, we play-in patterns of population and projection activity to test causal impact on behavior. And in Aim 3, we leverage the highest-resolution of our new methods, that nonetheless maintain broad perspective. We are now able to image (with OEG as well as resonant-scanning two-photon microscopy) large volumes of brain and quantify high-speed dynamical activity patterns that are cell type-specific, approaching single-cell resolution while maintaining map-like brainwide perspective, during behavior and during exposure to drugs of abuse. Interventional tests for causality will be directly guided by these observations. As described below, we have already observed highly specific cortical activity patterns in response to subanaesthetic ketamine doses, which here will be extended to the same drug and behavioral conditions pertaining to Aims 1 and 2. This precise observation and control of distinct neural circuit pathways is tightly intertwined with the research programs described in Projects 2-4, and the Technology and Training Cores. Together, these experiments in Project 1 will test versatile, powerful new circuit-dynamics tools for use in the NIDA Center and for the drug abuse community more broadly, and will also apply these tools to deepen our understanding of acute or chronically-altered drug altered states, and of the brain itself as a dynamical system.