Functional Imaging of The Brain

大脑功能成像

• 批准号: 10708602
• 负责人: Alan Koretsky
• 金额: $ 218.94万
• 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/10708602
• 关键词: 1 year old; Address; Adult; Affect; Anatomy; Animals; Area; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Paradigm; Brain; Brain Diseases; Brain imaging; Brain region; Cells; Chemosensitization; Collaborations; Corpus Callosum; Coupling; Data; Denervation; Detection; Development; Electrophysiology (science); Embryo; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Gene Expression; Gene Expression Profiling; Goals; Growth; Head; Human; Image; Imaging Device; Imaging Techniques; Implant; Ipsilateral; Learning; Limb structure; Magnetic Resonance Imaging; Manganese; Maps; Measures; Molecular; Motor; Motor Pathways; Nerve; Neurons; Neurosciences; Nose; Odors; Olfactory Pathways; Output; Pathway interactions; Peripheral; Physiology; Population; Positioning Attribute; Process; Professional counselor; Regulation; Resolution; Rodent; Rodent Model; Site; Slice; Somatosensory Cortex; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Tissues; Translating; Transplantation; Vibrissae; Work; age effect; anatomic imaging; barrel cortex; base; brain tissue; cellular imaging; critical period; developmental plasticity; experimental study; frontal lobe; gray matter; hippocampal pyramidal neuron; image guided; improved; molecular imaging; nerve injury; nerve stem cell; nerve supply; neural; novel; olfactory bulb; optical imaging; precursor cell; recruit; repaired; response; response to injury; somatosensory; stellate cell; stem cells; subventricular zone; tool; white matter

Specific aims have been redefined after an outstanding Board of Scientific Counselors review of the work in April 2021. The overall goal of this work remains 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, learning and integration of tranplanted neural precursor cells in the rodent brain. MRI techniques are having a broad impact on understanding the brain. Anatomical based MRI has been very useful for distinguishing 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 circulit and system level changes that occur in the rodent brain during plasticity and learning. Aim 1: Over the past few years we established a rodent model that uses peripheral denervation to study brain plasticity in response to the injury. 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. Developments in fMRI (laminar specific fMRI) and manganese enhanced MRI for neural tracing by our group were able to predict a strengthening of thalamocortical input along the spared pathway which was verified in slice electrophysiology studies. Prior to this, it was widely believed that the thalamocortical input was not capable of strengthening after the critical period, but we have shown plasticity that mimics developmental plasticity can be reactivated. Preliminary single cell expression data indicates that there are four distinct populations of stellate cells: those that have marker gene expression changes indicating plasticity and those that do not indicate gene expression changes associated plasticity. Over the next period we hope to characterize these separate populations and determine if there is heterogeniety in plasticity. If cells can be distinguished, we will ask if responses are altered as expected from the gene expression analysis. A study was completed in collaboration with Sengsoo Chueng and Hyesoo Lee that indicated that the plasticity we have discovered is associated with faster learning and improved retention in a whisker roughness task. This establishes a behavioral correlate of this plasticity. In our own lab we have established a simple whisker task based on detection of pole position in a head fixed apparatus that can translate to future imaging experiments. We are in the process of determining whether the whisker plasticity affects pole position detection. In addition to thalamocortical plasticity, we have demonstrated a synaptic basis for cellular takeover by the spared whiskers of the denervated whisker 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. 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. Our ability to do whisker task behavior will let us address the functional significance of this plasticity. This opens the question of whether outputs from the intact cortex has been affected and whether information to other areas such M1 and S2 is altered. We will combine fMRI, MRI neural tracing techniques and electrophysioloy to address this question over the next period. Aim 2: A few years ago we discovered that cortical precursor cells can be grown in mature, brain tissue when implanted into the CSF. These tissues project to the host brain and the host brain projects to the tissue. We are completing an exciting study that characterizes the extent of host brain innervation and the effects of age on the interactions between host and brain-like tissues growing in the CSF space. We see effective integration of these precursor cells in up to one year old animals. We are also completing studies that show these tissues are functionally integrated into the host. Exciting results show these brain-like tissues can functionally couple to the olfactory system or the motor system of the host depending on where the tissue is grown. There is extensive reciprocal connections to frontal cortex and thalamic regions. The relevance of this functional coupling on behavior and the mechanism for how the host sends long distance projections into these tissues will be studied over the next period.

在科学顾问委员会于2021年4月对工作进行了出色的审查后，重新定义了具体目标。这项工作的总体目标仍然是开发解剖，功能和分子磁共振成像（MRI）技术，允许非侵入性评估脑功能，并应用这些工具来研究啮齿动物大脑中移植的神经前体细胞的可塑性，学习和整合。MRI技术对理解大脑有着广泛的影响。基于解剖的MRI对于区分灰色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是一个新兴的领域，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电路和系统水平的变化。 目的1：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。我们已经表明，眶下神经的去神经支配导致桶皮质反应的大幅度增加沿着备用胡须通路以及大同侧皮质活动与我们以前的工作一致，在前爪和后爪。我们小组在功能磁共振成像（层特异性功能磁共振成像）和锰增强磁共振成像神经示踪的发展能够预测加强丘脑皮质输入沿着备用通路，这是在切片电生理学研究中验证。在此之前，人们普遍认为，丘脑皮质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。初步的单细胞表达数据表明，有四个不同的群体的星状细胞：那些有标记基因表达的变化表明可塑性和那些不表明基因表达的变化相关的可塑性。在接下来的一段时间里，我们希望描述这些不同的人群，并确定是否有可塑性的异质性。如果可以区分细胞，我们将询问反应是否如基因表达分析所预期的那样改变。与Sengsoo Chueng和Hyesoo Lee合作完成的一项研究表明，我们发现的可塑性与更快的学习和改善胡须粗糙度任务的保持力有关。这建立了这种可塑性的行为相关性。在我们自己的实验室中，我们已经建立了一个简单的触须任务，基于头部固定装置中的极点位置检测，可以转化为未来的成像实验。我们正在确定触须的可塑性是否会影响极点位置检测。 除了丘脑皮层的可塑性，我们已经证明了一个突触的基础，通过胼胝体输入的备用晶须的去神经晶须S1桶皮质细胞接管。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。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。我们进行胡须任务行为的能力将使我们能够解决这种可塑性的功能意义。这就引出了一个问题，即来自完整皮层的输出是否受到了影响，以及传递给其他区域（如M1和S2）的信息是否被改变了。我们将结合联合收割机功能磁共振成像，磁共振成像神经跟踪技术和电生理学来解决这个问题在未来的一段时间。 目标2：几年前，我们发现皮质前体细胞可以在植入CSF时在成熟的脑组织中生长。这些组织投射到宿主脑，宿主脑投射到组织。我们正在完成一项令人兴奋的研究，该研究描述了宿主脑神经支配的程度以及年龄对宿主和CSF空间中生长的脑样组织之间相互作用的影响。我们看到这些前体细胞在长达一岁的动物中有效整合。我们还正在完成研究，表明这些组织在功能上整合到宿主中。令人兴奋的结果表明，这些类似大脑的组织可以在功能上与宿主的嗅觉系统或运动系统耦合，这取决于组织生长的位置。与额叶皮层和丘脑区域有广泛的相互联系。下一阶段将研究这种功能耦合对行为的相关性以及宿主如何向这些组织发送长距离投射的机制。