Single-cell causality in origination, propagation, and resolution of drug-altered brain states

药物改变大脑状态的起源、传播和解决的单细胞因果关系

• 批准号: 10494005
• 负责人: Karl A. Deisseroth
• 金额: $ 30.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494005
• 关键词: 3-Dimensional; Accounting; Acute; Affective; Animals; Area; Aversive Stimulus; Behavior; Behavioral; Brain; Cells; Chemistry; Chronic; Communities; Dependence; Desire for food; Development; Dissociation; Drug Modulation; Drug abuse; Elements; Epidemiology; Etiology; Exposure to; Extramural Activities; Fiber; Foundations; Funding; Hydrogels; Image; Individual; Intervention; Investigation; Ketamine; Link; Maps; Measures; Methamphetamine; Methods; Molecular; National Institute of Drug Abuse; Neurons; Opioid; Outcome; Pathway interactions; Pattern; Perception; Pharmaceutical Preparations; Photometry; Physiologic pulse; Play; Population; Predisposition; Prevention; Productivity; Program Description; Property; Publishing; Reagent; Research; Resolution; Rewards; Risk; Rodent; Sensory; Specificity; Substance abuse problem; Technology; Testing; Thalamic Nuclei; Therapeutic; Tissues; Training; Work; awake; behavioral response; clinically significant; drug action; drug of abuse; dynamic system; ecstasy; experimental study; insight; neural; neural circuit; novel; optogenetics; synergism; temporal measurement; therapeutic target; tool; transcriptomics

PROJECT SUMMARY (Project 1) Here we implement a technology-driven approach to identify and control circuit dynamics underlying drug- modulated 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 hydrogel-tissue chemistry including STARmap) 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 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 our population and projection-specific recording and intervention capability, 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 achieve single-cell resolution while maintaining map-like broad perspective, during behavior and during exposure to drugs of abuse. Interventional tests for causality will be directly guided by these observations, and will build upon both single-cell-resolution ensemble control and deep transcriptomic analysis of those individual cells. 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.

项目摘要（项目1） 在这里，我们实施了一种以技术为导向的方法来识别和控制药物的基础电路动态 - 在具有奖励和风险的上下文中调制行为。我们应用代表主要一致的技术 药物滥用研究的机会（光脑摄影或OEG，框架项目的独立纤维 光度法或FIP，以及包括星形的水凝胶 - 组织化学反应），不仅允许观察和 控制遗传定义的电路，但在 在毒品改变状态下的行为期间和之后。在AIM 1中，我们以最广泛的（全力）的比例开始 清醒啮齿动物，以公正的方式识别关键参与者和原则，同时保持电路元素 - 观察和控制活动的特异性。从技术上讲，AIM 1实验将包括光遗传学 - 驱动针对特定电路和投影的精确脉冲图案，以及快速和定量 评估精心的活动模式。这些最初的公正全球评估将有力地告知和 在AIM 2和3中重点进行了更多的空间限制研究，以解决急性改变的基本特征 国家。在AIM 2中，我们以更高的空间和时间分辨率运行，下一步迈向详细的一步 在急性改变药物的状态下阐明因果电路动力学。对于相同的药物和行为 AIM 1中的条件，现在以神经元活性水平为单个动物水平进行定量指导 使用我们的人群和特定于投影的记录和干预能力来定位，我们会播放模式 人口和投射活动以测试因果行为的影响。在AIM 3中，我们利用最高的 解决新方法的解决方案，这些方法可以实现单细胞分辨率，同时保持类似地图的广泛视角， 在行为和暴露于滥用药物的过程中。因果关系的介入测试将直接指导 通过这些观察结果，并将建立在单细胞分辨率集合控制和深度转录组上 分析这些单个细胞。这种不同的神经回路通路的精确观察和控制紧密 与项目2-4中描述的研究计划以及技术和培训核心交织在一起。 总之，这些项目1中的这些实验将测试用于多功能的，强大的新电路动力学工具，可用于 NIDA中心和毒品滥用社区的更广泛地，还将应用这些工具来加深我们 理解急性或长期改变的药物改变态，以及大脑本身作为动力学系统。