Functional Imaging of The Brain

大脑功能成像

基本信息

批准号：
10263021
负责人：
Alan Koretsky
金额：
$ 412.02万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263021
关键词：
Address Adult Anatomy Architecture Area Back Behavior Behavioral Behavioral Model Beta Cell Blood Volume Brain Brain Diseases Brain imaging Brain region Calcium Cells Collaborations Corpus Callosum Cortical Column Denervation Detection Development Electrophysiology (science)Freezing Functional Imaging Functional Magnetic Resonance Imaging Goals Head Hippocampus (Brain)Histologic Human Image Imaging Device Imaging Techniques Ipsilateral Lead Learning Magnetic Resonance Imaging Manganese Measures Modeling Molecular Monitor National Institute of Mental Health Nerve Nerve Degeneration Neurons Neurosciences Organ Output Paper Pathway interactions Pattern Peripheral Peripheral Nerves Persons Preparation Process Publications Publishing Reproducibility Resolution Rodent Rodent Model Slice Structure of beta Cell of islet Surrogate Markers Synapses Synaptic Vesicles System Techniques Tissues Transferable Skills Translating Vibrissae Work anatomic imaging arteriole barrel cortex base blood oxygenation level dependent response cellular imaging conditioned fear contrast imaging coronavirus disease critical period developmental plasticity experimental study gray matter hemodynamics hippocampal pyramidal neuron imaging properties manganese chloride molecular imaging nerve injury novel optical imaging relating to nervous system response response to injury tool white matter

项目摘要

The overall goal of this work is to develop anatomical, functional, and molecular magnetic resonance imaging (MRI) techniques that allow non-invasive assessment of brain function and apply these tools to study plasticity and learning in the rodent brain. MRI techniques are having a broad impact on understanding brain. Anatomical based MRI has been very useful for separating gray and white matter and detecting numerous brain disorders. Functional MRI techniques enable detection of regions of the brain that are active during a task. Molecular MRI is an emerging area, whose major goal is to image a large variety of processes in tissues. The goal of this project is to translate MRI developments in all these areas to study system level changes that occur in the rodent brain during plasticity and learning. Aim 1: Progress has been slow in this aim because a fellow has gotten distracted by a new project and a second fellow has just recently joined just prior to COVID. Over the past few years, we have completed studies in the rodent brain that acquired very high temporal and spatial resolution functional MRI (fMRI) to monitor changes in hemodynamics as a surrogate marker of electrical activity during forepaw stimulation. We have demonstrated that fMRI from single venuoles can be detected with BOLD fMRI and that single arterioles from deep cortex can be effectively imaged using blood volume based MRI techniques. In related work we have demonstrated that initial BOLD response coincides with the neural input to the cortex. This has led to the idea that at high spatial resolution MRI can get laminar specific information. This past year there have been a number of studies from a number of different labs that indicate these ideas will transfer to human fMRI. We have begun studies to measure the onset distribution through the cortex of arteriole volume and to determine if we can measure the rate of back propagation of arteriole dilation from its origin through the cortical column. This is critical parameter to help interpret laminar specific fMRI. Aim 2: Over the past several years we have demonstrated that manganese (Mn) chloride enables MRI contrast that defines neural architecture, can monitor activity, can be used to trace neural connections and can be used to monitor neurodegeneration at a cytoarchitectural level. Much work using Manganese Enhanced MRI (MEMRI) has resulted in increasing our determination to understand mechanisms better. A study has been completed and submitted for publication that uses a hippocampal slice preparation to study mechanisms of Mn transport. A second study is close to completion that uses isolated pancreatic beta cells in addition to brain slices to study the synaptic mechanisms underlying the MRI properties of manganese. This work, in collaboration with Richard Leapman, has been able to accomplish very high resolution localization of Mn to synaptic vesicles in neurons and beta cells in frozen tissue helping to validate the model which had been hypothesized that Mn is released at synapses. We have begun a new project determine the cell distribution of Mn in brain and the transport systems responsible for this distribution. This will combine near cellular high resolution MRI (35-50 microns) with advanced histological tools to understand the cellular basis of MEMRI. Aim 3: Over the past few years we established a rodent model that uses peripheral denervation to study brain plasticity in response to the injury. Over the past couple of years we have shown that denervation of the infraorbital nerve leads to large increases in barrel cortex responses along the spared whisker pathway as well as large ipsilateral cortical activity consistent with our previous work in the forepaw and hindpaw. fMRI and manganese enhanced MRI predicted a strengthening of thalamo-cortical input along the spared pathway which was verified in slice electrophysiology studies in collaboration with John Isaac. Prior to this it was widely believed that the thalamo-cortical input was not capable of strengthening after the critical period but we have shown plasticity that mimics developmental plasticity can be reactivated. Two major questions are: Are more layer 4 stellate neurons firing to the same stimulation?; and, is the relative distribution of S1 output to S2 and M1 altered. We are addressing these questions with fluorescent Calcium imaging. We have published two major papers detailing cellular mechanism for takeover by the good whiskers of the denervated whiskers S1 barrel cortex via the corpus callosum input. This input can undergo LTP in the adult and the callosal inputs are strengthened on to layer 5 pyramidal neurons. This strengthening is so large that this synapse can no longer undergo LTP. We have completed a second paper that shows that this plasticity is very different depending on which area of the brain that the layer 5 neuron sends outputs. This is compelling evidence that this plasticity may have specific functional consequences. Armed with the synaptic changes occurring, we have begun to do head fixed whisker behavior tasks to address the issue of the behavioral consequences of this plasticity We will move these behavioral models into the MRI so that whole brain activity patterns can be measured. Aim 4: Progress in this aim continues to be slow due to lack of a specific person to carry out the work. We have re-established our ability to do fear condition experiments with a new behavioral set-up which was built to be consistent with the new NIMH Behavioral Core behavior enabling easy transfer of skills. We are validating that earlier Mn tracing experiments that indicated plasticity at novel synapses during fear conditioning are reproducible. If so we will take the approach as Aim 3 to determine the synaptic basis for the changes using slice electrophysiology.

这项工作的总体目标是开发解剖学、功能性和分子磁共振成像 (MRI) 技术，允许对大脑功能进行非侵入性评估，并应用这些工具来研究啮齿动物大脑的可塑性和学习能力。 MRI 技术对理解大脑产生了广泛的影响。基于解剖学的 MRI 对于分离灰质和白质以及检测多种脑部疾病非常有用。功能性 MRI 技术能够检测任务期间活跃的大脑区域。分子 MRI 是一个新兴领域，其主要目标是对组织中的各种过程进行成像。该项目的目标是将 MRI 的发展转化为所有这些领域的成果，以研究啮齿动物大脑在可塑性和学习过程中发生的系统级变化。目标 1：该目标进展缓慢，因为一名研究员因新项目而分心，而另一名研究员最近在新冠疫情爆发之前刚刚加入。在过去的几年里，我们完成了啮齿类动物大脑的研究，获得了非常高的时间和空间分辨率的功能性 MRI (fMRI)，以监测血流动力学的变化，作为前爪刺激期间电活动的替代标志。我们已经证明，可以使用 BOLD fMRI 检测来自单小静脉的 fMRI，并且可以使用基于血量的 MRI 技术对来自深层皮层的单小动脉进行有效成像。在相关工作中，我们已经证明初始 BOLD 反应与皮层的神经输入一致。这引发了这样的想法：在高空间分辨率 MRI 下可以获得层状特定信息。去年，来自多个不同实验室的大量研究表明这些想法将转移到人类功能磁共振成像中。我们已经开始研究测量小动脉体积通过皮层的起始分布，并确定是否可以测量小动脉扩张从其起点通过皮层柱的反向传播速率。这是帮助解释层流特异性功能磁共振成像的关键参数。目标 2：在过去的几年中，我们已经证明，氯化锰 (Mn) 能够实现 MRI 对比，从而定义神经结构，可以监测活动，可以用于追踪神经连接，并可以用于在细胞结构水平上监测神经退行性变。使用锰增强 MRI (MEMRI) 进行的大量工作增强了我们更好地理解机制的决心。一项研究已经完成并提交发表，该研究使用海马切片制剂来研究锰转运机制。第二项研究即将完成，除了脑切片之外，还使用分离的胰腺 β 细胞来研究锰的 MRI 特性背后的突触机制。这项工作与 Richard Leapman 合作，已经能够实现 Mn 对神经元突触小泡和冷冻组织中 β 细胞的高分辨率定位，有助于验证 Mn 在突触释放的假设模型。我们已经开始了一个新项目，确定大脑中锰的细胞分布以及负责这种分布的运输系统。这将把近细胞高分辨率 MRI（35-50 微米）与先进的组织学工具结合起来，以了解 MEMRI 的细胞基础。目标 3：在过去的几年里，我们建立了一个啮齿动物模型，利用周围去神经来研究大脑对损伤的可塑性。在过去的几年里，我们已经证明，眶下神经的去神经支配会导致沿幸存的胡须通路的桶状皮层反应大幅增加，以及同侧皮层活动的大量增加，这与我们之前在前爪和后爪的工作一致。功能磁共振成像和锰增强磁共振成像预测丘脑皮质输入沿着幸存的通路增强，这一点在与约翰·艾萨克合作的切片电生理学研究中得到了验证。在此之前，人们普遍认为丘脑皮质输入在关键期后无法强化，但我们已经证明了模仿发育可塑性的可塑性可以重新激活。两个主要问题是：是否有更多的第 4 层星状神经元受到相同的刺激？并且，是 S1 输出到 S2 和 M1 改变的相对分布。我们正在通过荧光钙成像来解决这些问题。我们发表了两篇重要论文，详细介绍了去神经须 S1 桶状皮质的好须通过胼胝体输入接管的细胞机制。这种输入在成人中可以经历 LTP，并且胼胝体输入在第 5 层锥体神经元上得到加强。这种强化是如此之大，以至于该突触无法再进行 LTP。我们已经完成了第二篇论文，表明这种可塑性根据第 5 层神经元发送输出的大脑区域而有很大不同。这是令人信服的证据，表明这种可塑性可能会产生特定的功能后果。随着突触变化的发生，我们已经开始进行头部固定胡须行为任务，以解决这种可塑性的行为后果问题。我们将把这些行为模型转移到 MRI 中，以便可以测量整个大脑的活动模式。目标 4：由于缺乏具体人员来开展这项工作，该目标的进展仍然缓慢。我们通过新的行为设置重新建立了进行恐惧条件实验的能力，该设置的建立与新的 NIMH 行为核心行为一致，可轻松转移技能。我们正在验证早期的锰示踪实验，该实验表明恐惧条件反射期间新突触的可塑性是可重复的。如果是这样，我们将采用目标 3 的方法，使用切片电生理学确定突触基础。