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

• 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
• 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' 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

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性的波动，从而塑造大脑的整体活动状态 优化细胞和电路活动。这种大脑状态依赖的细胞和分子机制 神经活动的调节尚不清楚。使用鼠标移动范例，我们最近 发现从静止状态到主动运动的转变与释放 神经递质去甲肾上腺素并导致星形胶质细胞的 Ca2+ 激活。星形胶质细胞被激活 同时在小脑和初级视觉皮层等不同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调节中发挥重要作用。精确的 运动诱导星形胶质细胞Ca2+激活的分子机制及其后果 成人大脑中的神经元活动尚不清楚。在这个项目中，我们将测试运动的假设 神经元活动的诱导去甲肾上腺素能调节是由星形胶质细胞介导的。我们将应用组合 体内双光子 Ca2+ 成像和电生理学的研究，以及特定小鼠的急性切片实验 以细胞类型特异性方式进行基因改造的细胞系，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。我们的研究重点将是 小脑皮层利用仅由少数细胞组成的电路。一个新颖的应用 特定的 Cre 小鼠品系将使我们能够选择性地操纵伯格曼神经胶质细胞，同时保留软腭 小脑皮质的星形胶质细胞不受干扰。我们将追求以下目标：（一）结合 我们将使用全局和细胞类型特异性敲除小鼠进行免疫细胞化学和功能研究 确定运动诱导的伯格曼胶质细胞 Ca2+ 激活所需受体的身份和位置。 (2) 我们将研究浦肯野神经元中运动诱导的 Ca2+ 和电信号，浦肯野神经元是主要的神经元。 小脑皮质的神经元。通过基因消除伯格曼神经胶质细胞整体 Ca2+ 升高，我们将 分离由先前的伯格曼神经胶质细胞引起的运动诱导的浦肯野神经元信号传导的成分 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要神经元活动依赖性的分子机制 关于行为状态。小脑伯格曼神经胶质细胞与帆状星形胶质细胞具有许多相同的功能特性 大脑的其余部分，包括运动引起的、去甲肾上腺素依赖性的全局 Ca2+ 激活。 因此，我们预计我们的机制研究将对理解星形胶质细胞的作用具有指导意义 整个大脑的大脑状态依赖性去甲肾上腺素能神经调节。这项工作将构建 为未来研究神经退行性疾病和脑状态依赖性神经信号传导奠定基础 与去甲肾上腺素能信号变化相关的神经行为状况，例如阿尔茨海默病， 帕金森病和自闭症。