Noradrenergic regulation of grey-matter astrocyte maturation

灰质星形胶质细胞成熟的去甲肾上腺素能调节

• 批准号: 10428578
• 负责人: Marci Rosenberg
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428578
• 关键词: Adrenergic Agents; Adrenergic Receptor; Adult; Affect; Animals; Arousal; Astrocytes; Axon; Behavior; Brain; CRISPR interference; Calcium; Cells; Complex; Connexins; Cues; Data; Development; Diffuse; Disease; Electroporation; Environment; Excitatory Synapse; Exhibits; Experimental Models; Functional disorder; GJB6 gene; Glial Fibrillary Acidic Protein; Glutamates; Impairment; In Vitro; Intermediate Filament Proteins; Knock-out; Label; Ligands; Link; Modeling; Molecular; Morphology; Mus; Neuraxis; Neuromodulator; Neurons; Norepinephrine; Pharmacology; Phenocopy; Plasmids; Play; Population; Process; Proteins; Receptors, Adrenergic, beta-1; Recycling; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Specific qualifier value; Stains; Stress; Synapses; Synaptic Cleft; Testing; Toxin; Wakefulness; beta-adrenergic receptor; density; excitatory neuron; gray matter; in vivo; insight; knockout animal; locus ceruleus structure; neuroligin 2; noradrenergic; novel; patch clamp; postnatal period; postsynaptic; synaptic function; synaptogenesis; transcriptomics; uptake; white matter

PROJECT ABSTRACT: Appropriate synapse formation and maturation are critical processes contributing to brain development. We now know that synaptic connections between neurons are extensively affected by astrocytes. Astrocytes, by virtue of their elaborate synapse-associated processes, in conjunction with secreted molecules, promote synapse formation, enhance synapse maturation, and regulate synapse elimination. Alterations in astrocyte morphology have repeatedly been shown to lessen the number and/or strength of excitatory synapses. However, not all astrocytes are associated with synapses. A single grey-matter astrocyte can encompass tens of thousands of synapses within its complex, highly branched arbor. In contrast, less-branched white-matter astrocytes are located in regions of low synapse density. The molecular mechanisms by which astrocyte identity is specified and maintained are largely unknown. In a screen of molecules enriched in developing grey-matter vs. white-matter astrocytes, we identified adrenergic receptors as preferentially enriched in the grey-matter astrocyte population. This suggests that norepinephrine may be an important positive modulator of grey-matter astrocyte maturation. Preliminary evidence in this proposal shows that astrocytes express the beta 1 adrenergic receptors. Stimulation of beta-adrenergic receptors increases astrocyte primary branching in vitro, while depletion of norepinephrine or beta-adrenergic receptors in vivo causes cortical grey-matter astrocytes to exhibit reduced morphologic complexity, along with reduced expression of grey-matter astrocyte markers. This proposal will test the hypothesis that norepinephrine signals through astrocytic beta-adrenergic receptors to increase morphologic complexity, which in turn increases their capacity to support synapse formation and function. Aim 1 will use global and astrocyte-specific conditional deletion of the beta 1 adrenergic receptor to determine whether beta-adrenergic signaling drives astrocyte morphologic complexity and molecular identity. Aim 2 will use the same experimental models to identify the impact of beta-adrenergic signaling on the development of cortical excitatory synapses. Data from these aims will elucidate how norepinephrine, a ubiquitous neuromodulator dynamically altered in processes such as arousal and stress, influences the development of grey-matter astrocytes and their ability to promote excitatory synapse development in the cortex.

项目摘要： 适当的突触形成和成熟是大脑发育的关键过程。我们现在 神经元之间的突触连接受到星形胶质细胞的广泛影响。星形胶质细胞，凭借 它们精心设计的突触相关过程，与分泌的分子一起， 形成，增强突触成熟，并调节突触消除。星形胶质细胞形态的改变 已经反复显示减少兴奋性突触的数量和/或强度。但并非所有 星形胶质细胞与突触有关。单个灰质星形胶质细胞可以包含数万个 在其复杂的，高度分支的乔木内的突触。相比之下，较少分支的白质星形胶质细胞 位于突触密度低的区域。星形胶质细胞特性的分子机制 和维护的基本上是未知的。 在对发育中的灰质和白质星形胶质细胞中富集的分子进行筛选时，我们鉴定出肾上腺素能 受体优先富集在灰质星形胶质细胞群体中。这表明去甲肾上腺素 可能是灰质星形胶质细胞成熟的重要正调节剂。初步证据显示 该提案表明星形胶质细胞表达β 1肾上腺素能受体。β-肾上腺素能刺激 受体增加体外星形胶质细胞的初级分支，而去甲肾上腺素或β-肾上腺素能受体的耗竭， 受体在体内导致皮质灰质星形胶质细胞表现出降低的形态复杂性，沿着 灰质星形胶质细胞标记物表达减少。这项提议将检验去甲肾上腺素 通过星形胶质细胞β-肾上腺素能受体信号增加形态复杂性，这反过来又增加 它们支持突触形成和功能的能力。Aim 1将使用全局和星形胶质细胞特异性条件 β 1肾上腺素能受体的缺失，以确定β-肾上腺素能信号是否驱动星形胶质细胞 形态复杂性和分子同一性。目标2将使用相同的实验模型来确定 β-肾上腺素能信号对皮质兴奋性突触发育的影响。这些目标的数据 将阐明去甲肾上腺素，一种普遍存在的神经调节剂，如何在唤醒等过程中动态改变， 和压力，影响灰质星形胶质细胞的发育及其促进兴奋性突触的能力 皮层的发育。