Pan-neuronal functional imaging and anesthesia

全神经元功能成像和麻醉

基本信息

批准号：
9707361
负责人：
Christopher W Connor
金额：
$ 15.19万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9707361
关键词：
Absence of pain sensation Amnesia Anesthesia procedures Anesthesiology Anesthetics Animals Architecture Behavior Behavioral Paradigm Biological Models Brain Brain region Caenorhabditis elegans Calcium Clinical Complex Data Defect Electroencephalography Fluorescence Functional Imaging Functional Magnetic Resonance Imaging Ganglia General Anesthesia Genetic Glare Human Image Individual Knowledge Lead Longevity Maps Measurement Measures Mediating Medicine Memory Microscopy Modernization Modification Molecular Molecular Analysis Movement Mus Muscle relaxation phase Nematoda Nervous system structure Neurons Optics Pain Patients Perception Physiological Physiology Population Postoperative Period Psyche structure Research Resolution Risk Sensory Signal Transduction Somatosensory Cortex Stimulus System Techniques Technology Testing Time Transgenic Organisms Translating Translations Unconscious State calcium indicator clinical practice experience experimental study fluorescence imaging hippocampal pyramidal neuron in vivo mouse model neuronal circuitry novel optical imaging promoter receptor response theories two-photon

项目摘要

Abstract Volatile anesthetics produce all stages of general anesthesia including unconsciousness, amnesia, analgesia and muscle relaxation. Once placed into this physiological state, the experience, memory and physical response to excruciating pain are all lost. However, we still do not understand mechanistically how this state of anesthesia is produced within neuronal systems such that complex mental activity is ablated while vestigial physiology is preserved. To date, research has proceeded along essentially two tracks: either the gross measurement of neuronal activity in entire regions of the brain using fMRI and EEG (which are fundamentally limited by resolution), or analysis at the molecular level looking for specific receptors for the volatile anesthetics (which has largely foundered). Astonishingly, patients can nevertheless be promptly retrieved from this state, and empirical clinical practice has reduced the risk of anesthesia to the extent that it is now an essential and universally accepted part of the modern practice of medicine. Fortunately, using novel fluorescent microscopy, we are now able to image neuronal activity in real-time, in vivo, and at resolutions capable of simultaneously capturing the activity of individual neurons and entire populations of complex neuronal networks. In this study, we apply this technique to C. elegans in which we are able to capture the activity of the entire nervous system, and to the mouse in which we capture regions of the somatosensory cortex. To discern the effect by which clinical anesthesia is achieved, it would make sense to begin with the creature with the simplest, most tractable neuronal architecture in which anesthesia is known to be inducible. C. elegans offers a simple well-mapped nervous system (302 neurons), well characterized behavioral paradigms and amenable genetics. Moreover C. elegans is well established as a model system in anesthesiology, and displays distinct stages of gross behavior under anesthesia similar to humans. Using GCaMP, a fluorescent indicator of intracellular calcium concentration expressed transgenically under a neuronal promoter, we can capture the activity of multiple neurons optically, non-invasively, and in parallel. Our experimental system will allow us to measure activity of the individual neurons within large-scale neuronal circuits to understand how subtle modifications in discrete neuronal dynamics lead to the gross but reversible functional defects at the level of the overall nervous system that result in analgesia and physical quiescence. Our study will define the effects of volatile anesthetics over increasing neuronal complexity from individual neurons to the entire nervous system. Current technology within mammalian systems is limited in scale to small subsections of the brain. We will begin complementary imaging experiments in the somatosensory cortex of the mouse that will initiate the translation of our findings and techniques to mammalian systems.

抽象的挥发性麻醉剂会产生全身麻醉的所有阶段，包括无意识，健忘症，镇痛和肌肉放松。一旦进入这种生理状态，经验，记忆和身体对痛苦的反应都消失了。但是，我们仍然不理解这种状态麻醉是在神经元系统中产生的，因此复杂的心理活动是消融的。保留了生理学。迄今为止，研究已经沿着两条曲目进行：使用fMRI和EEG测量大脑整个区域的神经元活性（从根本上是受到分辨率的限制），或在分子水平上分析，寻找挥发性麻醉的特定受体（在很大程度上成立了）。令人惊讶的是，患者仍然可以迅速从该州检索到经验临床实践已将麻醉的风险降低到现在是必不可少的和现代医学实践中普遍接受的一部分。幸运的是，使用新型的荧光显微镜，现在，我们能够实时，体内和能够同时的分辨率进行神经元活动图像捕获复杂神经元网络的单个神经元和整个种群的活性。在这项研究中，我们将此技术应用于秀丽隐杆线虫，我们能够捕获整个神经系统的活动，以及捕获体感皮质区域的鼠标。辨别效果实现了临床麻醉，从最简单，最可行的生物开始是有意义的已知麻醉的神经元结构是可诱导的。秀丽隐杆线虫提供了简单的图像神经系统（302个神经元），表征良好的行为范式和可正常的遗传学。而且C. 秀丽隐杆线被确定为麻醉学中的模型系统，并显示出明显的总阶段麻醉下的行为类似于人类。使用GCAMP，一个细胞内钙的荧光指标在神经元启动子下以转基因表达的浓度，我们可以捕获多个的活性神经元在光学上，非侵入性和并行。我们的实验系统将使我们能够测量大规模神经元电路中的单个神经元，以了解离散的微妙修饰神经元动力学导致总体神经系统水平的总体但可逆的功能缺陷这会导致镇痛和身体静止。我们的研究将定义挥发性麻醉药的影响从单个神经元到整个神经系统的神经元复杂性增加。当前的技术内部哺乳动物系统的规模限制在大脑的小小节上。我们将开始补充小鼠体感皮层中的成像实验将启动我们的发现的翻译和哺乳动物系统的技术。