Noradrenergic regulation of grey-matter astrocyte maturation

项目摘要： 适当的突触形成和成熟是促进大脑发育的关键过程。我们现在 要知道，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 它们复杂的突触相关过程，与分泌的分子一起，促进突触 形成，促进突触成熟，调节突触消除。星形胶质细胞的形态变化 已经多次被证明可以减少兴奋性突触的数量和/或强度。然而，并不是所有的 星形胶质细胞与突触有关。一个单一的灰质星形细胞可以包含数万个 在其复杂的、高度分枝的乔木内有突触。相比之下，分支较少的白质星形胶质细胞 位于突触密度较低的区域。确定星形胶质细胞特性的分子机制 并维持在很大程度上是未知的。 在灰质和白质星形胶质细胞发育丰富的分子筛选中，我们确定了肾上腺素能 受体主要集中在灰质星形胶质细胞中。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向调节因子。这件事的初步证据 研究表明，星形胶质细胞表达β1肾上腺素能受体。刺激β-肾上腺素能 受体在体外增加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 体内受体导致皮质灰质星形胶质细胞表现出降低的形态复杂性， 灰质星形胶质细胞标志物表达减少。这项提议将检验去甲肾上腺素 通过星形细胞β-肾上腺素能受体的信号增加了形态的复杂性，进而增加了 它们支持突触形成和功能的能力。目标1将使用全局和特定于星形胶质细胞的条件 删除β1肾上腺素能受体以确定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层兴奋性突触发育的影响。来自这些目标的数据 我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变化 和应激，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 大脑皮层的发育。

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.