Regulation of adult hippocampal function by the neural stem and progenitor cell secretome

在成年的海马体中有一个独特的神经源性小生境，它拥有神经谱系干细胞，可以在整个脑海马体中存活。 各种成年哺乳动物的寿命。揭示这些干细胞的功能作用以及它们是如何 与小生境中其他类型的细胞相互作用可以提供对调节海马区的机制的洞察 认知-情绪功能，以及成人大脑中再生组织的潜在机制。 最近，干细胞分泌蛋白(即干细胞分泌组)已经成为组织中有影响力的参与者。 动态平衡。然而，无论是分泌体的内容还是功能都相对知之甚少。 成体海马区的内源性神经干细胞及其前体细胞。我们的初步数据 提示成年大鼠海马NSPC可能通过产生可溶性物质来调节微环境 蛋白质，血管内皮生长因子(VEGF)。我们发现NSPC在体内合成大量的血管内皮生长因子。 他们的海马区和NSPC衍生的血管内皮生长因子是维持健康的海马区功能所必需的。 我们建议研究NSPC通过血管内皮生长因子的直接作用支持海马区功能的假说 抑制神经元的超兴奋性，最终支持记忆功能，并保护它不受 受伤。在目标1中，我们将使用RNA测序以及遗传密码扩展与双正交非 用标准氨基酸蛋白质标记法确定NSPC对血管内皮生长因子亚型的局部特异性贡献 在这些细胞所在的齿状回亚区的细胞层中。在目标2中，我们将使用转基因 基因敲除和病毒拯救模型研究齿状回电路活动是如何被特异性地 NSPC来源的血管内皮生长因子。在目标3中，我们将使用转基因击倒和病毒救援模型来确定如何 NSPC-VEGF影响海马区行为功能和对兴奋性毒性损伤的易感性。完成度 这项工作将通过内源性NSPC的分泌组建立一个新的功能维度，并推动 了解如何在成人大脑的一个独特的利基环境中积极维持海马体的健康。

A unique neurogenic niche in the adult hippocampus hosts neural-lineage stem cells that can persist throughout the lifespan in a wide range of adult mammals. Uncovering the functional role of these stem cells and how they interact with other cell types in the niche can provide insight in to the mechanisms that mediate hippocampal cognitive-emotional functions, as well as potential mechanisms for regenerating tissue in the adult brain. Recently, stem cell secreted proteins (i.e. the stem cell secretome) have emerged as influential players in tissue homeostasis. However, relatively little is known about either the content or the function of the secretome of endogenous neural stem cells and their progenitors (NSPCs) in the adult hippocampus. Our preliminary data reveal that adult hippocampal NSPCs may regulate their microenvironment through the production of the soluble protein, vascular endothelial growth factor (VEGF). We find that NSPCs synthesize large quantities of VEGF in their hippocampal niche and that NSPC-derived VEGF is necessary for sustaining healthy hippocampal function. We propose to investigate the hypothesis that NSPCs support hippocampal function by direct actions of VEGF that suppress neuronal hyperexcitability, ultimately supporting memory function, as well as protecting it from injury. In Aim 1, we will use RNAsequencing as well as genetic code expansion coupled with biorthogonal non- canonical amino acid protein tagging to determine the specific local contributions of NSPCs to VEGF isoforms in the cell layers of the dentate gyrus subregion where these cells reside. In Aim 2, we will use transgenic knockdown and viral rescue models to investigate how dentate gyrus circuit activity is regulated specifically by NSPC-derived VEGF. In Aim 3, we will use transgenic knockdown and viral rescue models to determine how NSPC-VEGF influences hippocampal behavioral functions and vulnerability to excitotoxic injury. The completion of this work will establish a new functional dimension of endogenous NSPCs via their secretome, and advance understanding of how hippocampal health is actively maintained in a unique niche of the adult brain.