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，功能和分子磁共振成像（MRI）技术，该技术允许对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中的可塑性和学习。 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和检测许多脑部疾病非常有用。功能性MRI技术可以检测任务过程中活性的大脑区域。分子MRI是一个新兴区域，其主要目标是对组织中的各种过程进行成像。该项目的目的是将所有这些领域的MRI开发转换为研究在可塑性和学习过程中啮齿动物大脑中发生的系统水平变化。 AIM 1：在这个目标中进步很慢，因为一个家伙已经被一个新项目分心，而第二个同伴在Covid之前就加入了。在过去的几年中，我们已经完成了在啮齿动物大脑中的研究，这些研究获得了非常高的时间和空间分辨率功能性MRI（fMRI），以监测血液动力学的变化，作为前鹰刺激过程中电活动的替代标志物。我们已经证明，可以用大胆的fMRI检测到来自单个Venuoles的fMRI，并且可以使用基于血液体积的MRI技术有效地对来自深层皮质的单小动脉进行摄入。在相关工作中，我们证明了最初的粗体反应与皮质的神经输入相吻合。这导致了这样一个想法，即在高空间分辨率下，MRI可以获取层流特定的信息。在过去的一年中，许多不同的实验室进行了许多研究，这些研究表明这些想法将转移到人类fMRI。我们已经开始研究通过小动脉体积的皮质来测量发作分布，并确定我们是否可以通过皮质柱从其起源来测量小动脉扩张的背部传播速率。这是有助于解释层流特异性fMRI的关键参数。目标2：在过去的几年中，我们证明了锰（MN）氯化物实现了定义神经结构，可以监测活动的MRI对比度，可用于追踪神经连接，可用于在细胞构造水平上监测神经变性。使用锰增强MRI（MEMRI）的大量工作导致我们提高了更好地理解机制的决心。一项研究已经完成并提交了出版，该出版物使用海马切片制剂来研究MN运输的机制。第二项研究接近完成，除了大脑切片外，还使用了分离的胰腺β细胞来研究锰MRI特性的突触机制。这项工作与理查德·莱普曼（Richard Leapman）合作，已经能够完成在冷冻组织中神经元和β细胞中突触囊泡的高分辨率定位，有助于验证该模型，该模型已被假设在突触时释放了MN。我们已经开始了一个新项目，确定了大脑中MN的细胞分布以及负责此分布的运输系统。这将结合附近的细胞高分辨率MRI（35-50微米）与先进的组织学工具，以了解MEMRI的细胞基础。 AIM 3：在过去的几年中，我们建立了一种啮齿动物模型，该模型使用外围神经支配研究响应损伤的大脑可塑性。在过去的几年中，我们已经表明，对胸膜神经的神经神经的神经性会导致沿较大的晶须途径以及大型的同侧皮质活动沿着前言和汉德浦（Hindpaw）一致的大型同侧皮质活性。 fMRI和锰增强了MRI预测，沿着保险途径的丘脑皮层输入的加强，该途径在Slice电生理研究中与John Isaac合作进行了验证。在此之前，人们普遍认为，丘脑 - 皮质输入在关键时期无法加强，但是我们已经显示可塑性表明模仿发育可塑性可以重新激活。两个主要问题是：更多的第4层星状神经元发射到相同的刺激中？并且，S1输出对S2和M1的相对分布发生了变化。我们正在用荧光钙成像解决这些问题。我们已经发表了两篇主要论文，详细介绍了通过callosum callosum callosum callos的良好的晶须S1桶皮层的良好晶须的收购机制。该输入可以在成年人中经历LTP，并且将Callosal输入加强到第5层锥体神经元。这种加强是如此之大，以至于该突触不再能够经历LTP。我们已经完成了第二篇论文，该论文表明，根据5层神经元发送输出的大脑的哪个区域，这种可塑性非常不同。这是令人信服的证据，表明这种可塑性可能具有特定的功能后果。在发生突触变化的情况下，我们已经开始执行头部固定的晶须行为任务，以解决这种可塑性的行为后果问题，我们将将这些行为模型移至MRI中，以便可以测量整个大脑活动模式。 AIM 4：由于缺乏特定的人来执行工作，因此该目标的进展仍然很慢。我们已经通过新的行为设置重新建立了恐惧状况实验的能力，该设置与新的NIMH行为核心行为相一致，从而使技能易于转移。我们正在验证，早期的MN追踪实验表明在恐惧调节过程中新型突触的可塑性是可重现的。如果是这样，我们将采用该方法为目标3，以确定使用切片电生理学变化的突触基础。