The Role of Astroglia in Brain State-Dependent Neural Activity

星形胶质细胞在大脑状态依赖性神经活动中的作用

基本信息

批准号：
9918456
负责人：
Martin Paukert
金额：
$ 37.76万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918456
关键词：
Acute Adrenergic Receptor Adult Agonist Alzheimer&apos s Disease Astrocytes Attention Behavior Behavioral Behavioral Mechanisms Behavioral Paradigm Brain Brain region Cells Cerebellar Cortex Cerebellum Communication Coupled Coupling Data Dependovirus Electrophysiology (science)Elements Enterobacteria phage P1 Cre recombinase Foundations Future Genetic Goals Head Image Impairment Inositol Instruction Knock-out Knockout Mice Location Locomotion Measures Mediating Membrane Potentials Metabolic Modeling Molecular Mus Nerve Degeneration Neuroglia Neurons Norepinephrine Parkinson Disease Pharmacology Play Property Rest Role Shapes Signal Transduction Site Slice Structure of molecular layer of cerebellar cortex Synaptic plasticity Testing Time Transgenic Mice Work area striata autism spectrum disorder awake beta-Galactosidase cell type experimental study immunocytochemistry in vivo locus ceruleus structure metabotropic glutamate receptor type 1 mind control neurobehavioral neuroregulation neurotransmission neurotransmitter release noradrenergic novel receptor relating to nervous system response selective expression treadmill two photon microscopy two-photon vigilance

项目摘要

Awake behavior is accompanied by fluctuations in vigilance shaping the overall activity state of the brain to optimize cellular and circuit activity. The cellular and molecular mechanisms for such brain state-dependent adjustments in neural activity are not well understood. Using a mouse locomotion paradigm we have recently found that the transition from a resting state to active locomotion is associated with release of the neurotransmitter norepinephrine and leads to Ca2+ activation of astroglia. Astroglia are activated simultaneously in brain regions as disparate as the cerebellum and primary visual cortex suggesting that they might play a major role in mediating global brain state-dependent modulation of neural activity. The precise molecular mechanism of locomotion-induced astroglia Ca2+ activation as well as the consequences for neuronal activity in the adult brain are not known. In this project we will test the hypothesis that locomotion- induced noradrenergic modulation of neuronal activity is mediated by astroglia. We will apply a combination of in vivo two-photon Ca2+ imaging and electrophysiology, and acute slice experiments on specific mouse lines that have been genetically modified in a cell type-specific manner, to reveal the cellular and molecular mechanisms of astroglia-mediated, brain state-dependent neuromodulation. The focus of our studies will be on the cerebellar cortex leveraging on a circuit that consists only of a handful of cells. A novel application of a specific Cre mouse line will enable us to selectively manipulate Bergmann glia while leaving velate astrocytes of the cerebellar cortex unperturbed. We will pursue the following aims: (1) Combining immunocytochemistry and functional studies with global and cell type-specific knockout mice we will determine identity and location of receptors required for locomotion-induced Bergmann glia Ca2+ activation. (2) We will investigate locomotion-induced Ca2+ and electrical signals in Purkinje neurons, the principal neurons of the cerebellar cortex. Using genetic elimination of Bergmann glia global Ca2+ elevations we will isolate components of locomotion-induced Purkinje neuron signaling that are caused by prior Bergmann glia Ca2+ activation. (3) Combining pharmacology and cell type-specific knockout in slice experiments and in vivo, we will dissect the molecular mechanism how cerebellar astroglia impact principal neuron activity dependent on the behavioral state. Cerebellar Bergmann glia share many functional properties with velate astrocytes in the remainder of the brain, including locomotion-induced, norepinephrine-dependent global Ca2+ activation. Therefore, we anticipate that our mechanistic studies will be instructive for understanding the role of astroglia in brain state-dependent noradrenergic neuromodulation throughout the brain. This body of work will build the groundwork for future studies on brain state-dependent neural signaling under neurodegenerative and neurobehavioral conditions associated with changes in noradrenergic signaling, such as Alzheimer's disease, Parkinson's disease and autism.

清醒行为伴随着警惕的波动，使大脑的整体活动状态塑造到优化细胞和电路活性。这种大脑状态依赖性的细胞和分子机制神经活动的调整尚不清楚。使用鼠标运动范式我们最近有发现从静止状态到活动运动的过渡与释放有关神经递质去甲肾上腺素，并导致Astroglia的Ca2+激活。 Astroglia被激活同时在小脑和主要视觉皮层的大脑区域中，表明它们可能在介导全球大脑状态依赖性神经活动的调节中起主要作用。确切的运动引起的星形胶质细胞CA2+激活的分子机制以及对的后果成人大脑中的神经元活性尚不清楚。在这个项目中，我们将测试运动的假设诱导的神经元活性的去甲肾上腺素能调节是由星形胶质细胞介导的。我们将使用一个组合体内两光子Ca2+成像和电生理学的摄入量以及特定小鼠的急性切片实验以细胞类型特异性方式对基因修饰的线，以揭示细胞和分子星形胶质细胞介导的，大脑状态依赖性神经调节的机制。我们研究的重点将是在小脑皮层上利用仅由少数细胞组成的电路上。一个新颖的应用特定的CRE鼠标线将使我们能够选择性地操纵Bergmann Glia，同时离开Velate 小脑皮层的星形胶质细胞不受干扰。我们将追求以下目标：（1）合并全球和细胞类型特异性敲除小鼠的免疫细胞化学和功能研究我们将确定运动诱导的Bergmann Glia Ca2+激活所需的受体的身份和位置。（2）我们将研究机动诱导的Ca2+和Purkinje神经元中的电信号（主要）小脑皮质的神经元。使用遗传消除Bergmann Glia Global Ca2+高程我们将运动引起的Purkinje神经元信号传导的分离株成分是由先前的Bergmann Glia引起的 Ca2+激活。（3）在切片实验和体内结合药理学和细胞类型特异性敲除，我们将剖析小脑星形胶质细胞如何影响主神经元活性的分子机制在行为状态。小脑Bergmann Glia具有许多功能特性其余的大脑，包括运动诱导的，无肾上腺素依赖性的全局Ca2+激活。因此，我们预计我们的机械研究将具有启发性，以了解星形胶质细胞的作用在大脑状态依赖性去甲肾上腺素能神经调节中。这项工作将建立在神经退行性和与去甲肾上腺素能信号变化有关的神经行为条件，例如阿尔茨海默氏病，帕金森氏病和自闭症。