权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Astrocyte-neuron interactions in visual cortex circuits

视觉皮层回路中星形胶质细胞-神经元的相互作用

基本信息

批准号：
10092163
负责人：
MRIGANKA SUR
金额：
$ 46.26万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092163
关键词：
Address Affect Astrocytes Brain Brain Diseases Cell physiology Cells Cellular Structures Cerebral cortex Communication Complex Coupling Dendritic Spines Development Excitatory Synapse Generations Genetic Genetically Engineered Mouse Glutamate Transporter Glutamates Goals Image Imaging Techniques Immobilization Individual Measures Metabolic Mitochondria Mus Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Optics Pharmacology Photic Stimulation Physiological Play Process Property Recruitment Activity Regulation Research Resolution Role Shapes Signal Transduction Site Specificity Stimulus Structure Surface Synapses Synaptic Cleft Synaptic Transmission V1 neuron Vertebral column Visual Visual Cortex area striata awake excitatory neuron functional plasticity high resolution imaging imaging modality in vivo individual response information processing inhibitory neuron mitochondrial glutamate transporter monocular deprivation multiphoton imaging novel novel strategies orientation selectivity postsynaptic presynaptic protein expression response spatiotemporal transmission process uptake vision development visual processing visual stimulus

项目摘要

In primary visual cortex (V1), precise spatiotemporal neuronal responses are known to underlie visual processing. Though neuronal roles in visual processing have been well studied, the role of non-neuronal cells, particularly astrocytes, in cortical synapses and circuits remains poorly understood. Cortical astrocytes contact and ensheathe nearly all excitatory synapses, creating discrete functional units consisting of a presynaptic input, a postsynaptic spine and an astrocyte process. A crucial function of astrocytes is the active uptake of glutamate from the synaptic cleft via transporters, particularly GLT1. We propose that astrocytes contribute fundamentally to V1 circuits via GLT1 activity, actively shaping synaptic and neuronal response profiles. Focal Ca2+ transients potentially related to synaptic glutamate uptake have recently been demonstrated within astrocyte processes, and synaptic transmission shown to actively recruit astrocytic GLT1 to sites of synaptic activity. Novel high- resolution imaging techniques, together with cell-specific markers, new optical probes, and genetically engineered mice with specific temporal and spatial control of protein expression, enable us to analyze the crosstalk between astrocyte and neuronal activity at unprecedented resolution in awake mice in vivo. We aim to take advantage of the exquisite organization of visual inputs to V1 neurons to examine the interaction of Ca2+ microdomains, mitochondria and glutamate transporters in astrocyte processes, the functional contribution of astrocyte transporters to neuronal synapses and circuits during visual processing, and the impact of altered glutamate transport on the development and plasticity of V1 circuits. In Aim 1, we will examine astrocyte microdomain Ca2+ responses to visual stimuli, including orientation-specific gratings and complex natural images, their relationship to mitochondria, and how genetic or pharmacological reduction of GLT1 impacts the specificity and reliability of astrocyte and cell-specific neuronal responses. In Aim 2, we will determine the functional relationship between single dendritic spines and adjacent astrocytic processes using simultaneous dual-wavelength imaging of astrocytes and neurons during visual stimulation. We will also determine how GLT1 reduction affects astrocytic process and neuronal spine responses and structures. In Aim 3, we will determine the role of GLT1 in the development and plasticity of astrocyte responses and visual cortex circuits. We will examine how germline reduction of GLT1 alters neuronal and astrocyte microdomain responses during normal development and following monocular deprivation, along with the sharpening of orientation selectivity and the binocular matching of orientation preference. Our overarching goal is to critically examine the hypothesis that astrocytes and their transporters are integral functional partners with neurons in the function and development of cortical circuits. As such, an understanding of normal and abnormal function in a host of neurodevelopmental and neurodegenerative disorders will require incorporating the role of astrocytes.

在初级视觉皮层（V1）中，精确的时空神经元反应是视觉的基础加工。尽管神经元在视觉处理中的作用已得到充分研究，但非神经元细胞的作用，特别是星形胶质细胞，在皮质突触和回路中仍然知之甚少。皮质星形胶质细胞接触并包裹几乎所有兴奋性突触，创建由突触前输入组成的离散功能单元，突触后棘和星形胶质细胞过程。星形胶质细胞的一个重要功能是主动摄取谷氨酸通过转运蛋白，特别是 GLT1，从突触间隙排出。我们认为星形胶质细胞具有根本性的贡献通过 GLT1 活性连接至 V1 回路，积极塑造突触和神经元反应特征。局灶性 Ca2+ 瞬变最近在星形胶质细胞过程中证明了与突触谷氨酸摄取可能相关，突触传递可主动招募星形胶质细胞 GLT1 至突触活动部位。小说高分辨率成像技术，以及细胞特异性标记、新的光学探针和基因具有特定时间和空间控制蛋白质表达的工程小鼠，使我们能够分析在体内清醒的小鼠中，星形胶质细胞和神经元活动之间的串扰以前所未有的分辨率。我们的目标是利用 V1 神经元视觉输入的精致组织来检查 Ca2+ 的相互作用星形胶质细胞过程中的微结构域、线粒体和谷氨酸转运蛋白，其功能贡献在视觉处理过程中星形胶质细胞转运至神经元突触和回路，以及改变的影响谷氨酸转运对 V1 回路发育和可塑性的影响。在目标 1 中，我们将检查星形胶质细胞微域 Ca2+ 对视觉刺激的反应，包括特定方向的光栅和复杂的自然图像、它们与线粒体的关系，以及 GLT1 的遗传或药理学减少如何影响星形胶质细胞和细胞特异性神经元反应的特异性和可靠性。在目标 2 中，我们将确定使用同时分析单个树突棘和相邻星形胶质细胞过程之间的功能关系视觉刺激期间星形胶质细胞和神经元的双波长成像。我们还将确定 GLT1 如何减少影响星形胶质细胞过程和神经元脊柱反应和结构。在目标 3 中，我们将确定 GLT1 在星形胶质细胞反应和视觉皮层回路的发育和可塑性中的作用。我们将检查 GLT1 种系减少如何改变正常期间神经元和星形胶质细胞微区反应发展和单眼剥夺之后，随着方向选择性的锐化和方向偏好的双眼匹配。我们的首要目标是批判性地检验以下假设：星形胶质细胞及其转运蛋白是神经元功能和发育中不可或缺的功能伙伴的皮质回路。因此，了解许多神经发育的正常和异常功能神经退行性疾病需要结合星形胶质细胞的作用。