Functional characterization of neurotransmitter-mediated signaling in human neocortical development

人类新皮质发育中神经递质介导的信号传导的功能特征

• 批准号: 324874657
• 负责人: Dr. Simone Mayer
• 金额: --
• 依托单位: Department of Neurology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324874657?language=en
• 关键词: Functional; characterization; neurotransmitter; mediated; signaling

In evolutionary terms, the neocortex is the newest part of the mammalian brain and is the source of the complex cognitive skills of mammals. While the genome has been relatively stable, the neocortex has expanded significantly in the primate lineage. Both the number of cells and the number of different cell types in the neocortex has increased during the evolution of the human brain. The question therefore arises how the increased production of cells and the differentiation of different cell types is achieved during neocortical development. Previous research has shown that an enlarged repertoire of neural progenitor types underlies the generation of the larger number of neurons and glia that constitute the mature neocortex. However, how these neural progenitor cells maintain their proliferative potential throughout the extended neurogenic period in humans and how the large diversity of cell types is generated remains unknown. Studies in rodents have shown that neurotransmitter-mediated signaling in the developing brain regulates both the proliferation of neural progenitor cells and the differentiation of newborn neurons. We hypothesize that neurotransmitter-mediated intercellular signaling plays an even more important role in the development of the complex human brain. We therefore aim to study how the different neural progenitor cell types in the human brain are regulated by neurotransmitters. We will use changes in the concentration of intracellular calcium as a readout of the responsiveness of a cell to different neurotransmitters, since calcium is an important second messenger that links intercellular signaling to changes in transcription and thereby can alter cell fates. In Objective 1 we will characterize the physiological response profiles of human neural progenitor cells and newborn neurons to a range of different neurotransmitters. In Objective 2, we will use a novel high-throughput approach to link the physiological response profiles to cell types and states by analyzing single-cell transcriptomes. In Objective 3, we will study the long-term effects of neurotransmitter signaling on the proliferation and differentiation of different cell types by analyzing transcriptomes of single cells after neurotransmitter application and by studying changes in proliferation in tissue slices. This systems biology approach will allow us for the first time to elucidate how different cell types in the developing human neocortex regulate each other through neurotransmitter-mediated signaling. Since many neurodevelopmental disorders, such as autism spectrum disorders, are caused by mutations in genes that encode synaptic proteins, this research is instrumental for understanding how these mutations affect brain development even prior to the formation of synapses.

从进化的角度来看，新皮质是哺乳动物大脑的最新部分，也是哺乳动物复杂认知技能的来源。虽然基因组相对稳定，但灵长类谱系中的新皮质显着扩张。在人类大脑的进化过程中，新皮质中的细胞数量和不同细胞类型的数量都在增加。因此，问题是在新皮质发育过程中如何实现细胞产量的增加和不同细胞类型的分化。先前的研究表明，神经祖细胞类型的扩大是构成成熟新皮质的大量神经元和神经胶质细胞产生的基础。然而，这些神经祖细胞如何在人类延长的神经原性时期保持其增殖潜力以及如何产生大量细胞类型仍然未知。对啮齿动物的研究表明，发育中的大脑中神经递质介导的信号传导可调节神经祖细胞的增殖和新生神经元的分化。我们假设神经递质介导的细胞间信号传导在复杂的人脑发育中发挥着更重要的作用。因此，我们的目标是研究人脑中不同类型的神经祖细胞如何受到神经递质的调节。我们将使用细胞内钙浓度的变化作为细胞对不同神经递质的反应性的读数，因为钙是将细胞间信号传导与转录变化联系起来的重要第二信使，从而可以改变细胞命运。在目标 1 中，我们将描述人类神经祖细胞和新生神经元对一系列不同神经递质的生理反应特征。在目标 2 中，我们将使用一种新颖的高通量方法，通过分析单细胞转录组将生理反应谱与细胞类型和状态联系起来。在目标3中，我们将通过分析神经递质应用后单细胞的转录组以及研究组织切片中增殖的变化来研究神经递质信号传导对不同细胞类型增殖和分化的长期影响。这种系统生物学方法将使我们首次阐明发育中的人类新皮质中的不同细胞类型如何通过神经递质介导的信号传导相互调节。由于许多神经发育障碍（例如自闭症谱系障碍）是由编码突触蛋白的基因突变引起的，因此这项研究有助于了解这些突变甚至在突触形成之前如何影响大脑发育。

项目成果

Neuronal vulnerability and multilineage diversity in multiple sclerosis

• DOI: 10.1038/s41586-019-1404-z
• 发表时间: 2019-09-05
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Schirmer, Lucas;Velmeshev, Dmitry;Rowitch, David H.
• 通讯作者: Rowitch, David H.

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

• DOI: 10.1038/nature25975
• 发表时间: 2018-03-15
• 期刊: Nature
• 影响因子: 64.8
• 作者: Sorrells SF;Paredes MF;Cebrian-Silla A;Sandoval K;Qi D;Kelley KW;James D;Mayer S;Chang J;Auguste KI;Chang EF;Gutierrez AJ;Kriegstein AR;Mathern GW;Oldham MC;Huang EJ;Garcia-Verdugo JM;Yang Z;Alvarez-Buylla A
• 通讯作者: Alvarez-Buylla A

Single-cell genomics identifies cell type-specific molecular changes in autism.

• DOI: 10.1126/science.aav8130
• 发表时间: 2019-05-17
• 期刊: Science (New York, N.Y.)
• 作者: Velmeshev D;Schirmer L;Jung D;Haeussler M;Perez Y;Mayer S;Bhaduri A;Goyal N;Rowitch DH;Kriegstein AR
• 通讯作者: Kriegstein AR