Functional Imaging of The Brain

大脑功能成像

• 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
• 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

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，允许非侵入性评估大脑功能，并应用这些工具来研究啮齿动物大脑的可塑性和学习。MRI技术对理解大脑产生了广泛的影响。基于解剖学的MRI对于分离灰质和白色物质以及检测许多脑部疾病非常有用。功能性磁共振成像技术能够检测在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多种过程进行成像。该项目的目标是将MRI在所有这些领域的发展转化为研究啮齿动物大脑在可塑性和学习过程中发生的系统水平变化。 目标1：这一目标的进展一直很缓慢，因为一名研究员被一个新项目分心，另一名研究员最近刚刚在COVID之前加入。在过去的几年中，我们已经完成了啮齿动物大脑的研究，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电活动的替代标记物在前爪刺激。 我们已经证明，从单微静脉的功能磁共振成像可以检测到BOLD功能磁共振成像和单动脉从深层皮质可以有效地成像基于血容量的MRI技术。 在相关的工作中，我们已经证明，最初的BOLD反应与大脑皮层的神经输入相一致。这导致了这样一种想法，即在高空间分辨率下，MRI可以获得层流特异性信息。在过去的一年里，来自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，以测量通过皮质的小动脉体积的起始分布，并确定我们是否可以测量从其起源通过皮质柱的小动脉扩张的反向传播速率。这是帮助解释层特异性fMRI的关键参数。 目标二：在过去的几年里，我们已经证明，氯化锰（Mn）能够实现MRI对比度，定义神经结构，可以监测活动，可用于跟踪神经连接，并可用于监测细胞结构水平的神经变性。使用锰增强MRI（MEMRI）的许多工作增加了我们更好地了解机制的决心。 一项研究已经完成并提交出版，该研究使用海马切片制备来研究Mn转运机制。第二项研究接近完成，除了脑切片外，还使用分离的胰腺β细胞来研究锰的MRI特性的突触机制。这项工作与Richard Leapman合作，已经能够实现Mn在冷冻组织中的神经元和β细胞中的突触囊泡的非常高的分辨率定位，有助于验证假设Mn在突触处释放的模型。我们已经开始了一个新的项目，确定锰在大脑中的细胞分布和负责这种分布的运输系统。 这将结合联合收割机近细胞高分辨率MRI（35-50微米）与先进的组织学工具，以了解MEMRI的细胞基础。 目的3：在过去的几年里，我们建立了一个啮齿动物模型，使用外周去神经研究脑可塑性的损伤。在过去的几年里，我们已经表明，眶下神经的去神经支配导致桶皮层反应的大幅度增加，沿着备用胡须通路，以及大的同侧皮层活动与我们以前的工作一致，在前爪和后爪。 功能磁共振成像和锰增强磁共振成像预测了沿着备用通路的丘脑-皮层输入的加强，这在与John Isaac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-皮层输入是不能够加强后的关键时期，但我们已经表明可塑性，模仿发育可塑性可以重新激活。两个主要问题是：是否有更多的第4层星状神经元对同样的刺激放电？S_1输出相对于S_2和M_1的分配是否发生了变化。 我们正在解决这些问题与荧光钙成像。 我们已经发表了两篇主要论文，详细介绍了通过胼胝体输入由去神经胡须S1桶皮质的良好胡须接管的细胞机制。 这种输入在成年后可以经历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，以至于这个突触不能再经历LTP。 我们已经完成了第二篇论文，表明这种可塑性是非常不同的，这取决于大脑的哪个区域，第5层神经元发送输出。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。随着突触变化的发生，我们已经开始做头部固定胡须行为任务，以解决这种可塑性的行为后果的问题。我们将把这些行为模型转移到MRI中，这样就可以测量整个大脑的活动模式。 目标4：由于缺乏具体的人员开展工作，这一目标的进展仍然缓慢。 我们已经重新建立了我们的能力，做恐惧条件实验与新的行为设置，这是建立了符合新的NIMH行为核心行为，使技能容易转移。我们正在验证，早期锰示踪实验表明，在新的突触在恐惧条件反射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变化的突触基础。