Regulators of thyroid hormone action on adult hippocampal neurogenesis

甲状腺激素对成人海马神经发生的调节作用

• 批准号: 386971474
• 负责人: Dr. Steffen Mayerl
• 金额: --
• 依托单位: Klinik für Endokrinologie und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/386971474?language=en
• 关键词: Regulators; thyroid; hormone; action; adult

The hippocampal subgranular zone is one of only two areas that continue to generate new neurons in the adult brain. Over the last decade, the importance of this process for normal brain function was unequivocally demonstrated as deficits in hippocampal neurogenesis could clearly be linked to learning and memory impairments in humans and animal models. Adult hippocampal neurogenesis is a highly orchestrated process that involves the proliferation, differentiation, migration, and maturation of neural stem and progenitor cells to form functional granule cell neurons and that is governed by a variety of intrinsic and extrinsic signaling cues. Among the latter, thyroid hormones (THs) have been shown to regulate later stages of the neurogenic program in the adult hippocampus in animal models, and hypothyroidism in humans is associated with learning and memory defects linked to hippocampal neurogenesis. There is, however, only sparse information available about the progenitor stage-specific expression and function of various components of TH signaling. Here, I will elucidate the detailed expression of these components at different stages of the hippocampal neurogenic program in vivo and in vitro, and identify those that respond to changes in circulating TH levels in mouse models of hypo- and hyperthyroidism. Subsequently, I will investigate the in vivo relevance of TH signaling regulators engaged in the process by analyzing hippocampal neurogenesis in appropriate knockout animals, using both immunohistochemical and mRNA profiling techniques. In light of their learning deficits as well as morphological alterations in the hippocampus, mice lacking the TH transporters Mct8 and Oatp1c1 are the ideal starting point for these functional studies. In order to dissect stem cell/progenitor cell-intrinsic functions from global effects I will further generate and analyze mouse mutants that harbor deletions of TH signaling components specifically in the hippocampal lineage. Together, my results will not only provide new insights into the TH-dependent regulation of neural stem cells and progenitor cells in the hippocampus, but also contribute to the search for strategies to improve hippocampal neurogenesis in the aged population.

海马亚颗粒区是成人大脑中仅有的两个继续产生新神经元的区域之一。在过去的十年中，这一过程对正常脑功能的重要性得到了明确的证明，在人类和动物模型中，海马神经发生的缺陷可以清楚地与学习和记忆障碍联系起来。成人海马神经发生是一个高度协调的过程，涉及神经干细胞和祖细胞的增殖、分化、迁移和成熟，形成功能性颗粒细胞神经元，并受多种内在和外在信号提示的控制。在后者中，在动物模型中，甲状腺激素（THs）已被证明调节成年海马神经发生程序的后期阶段，人类甲状腺功能减退与海马神经发生相关的学习和记忆缺陷有关。然而，关于TH信号的各种成分的祖细胞阶段特异性表达和功能的信息很少。在这里，我将阐明这些成分在体内和体外海马神经发生程序的不同阶段的详细表达，并确定那些对甲状腺功能减退和甲亢小鼠模型中循环TH水平变化作出反应的成分。随后，我将利用免疫组织化学和mRNA谱分析技术，通过分析适当基因敲除动物的海马神经发生，研究TH信号调节因子参与该过程的体内相关性。鉴于它们的学习缺陷以及海马体的形态改变，缺乏TH转运体Mct8和Oatp1c1的小鼠是这些功能研究的理想起点。为了从全局效应中剖析干细胞/祖细胞的内在功能，我将进一步生成和分析海马谱系中含有TH信号成分缺失的小鼠突变体。总之，我的研究结果不仅将为海马中th依赖性神经干细胞和祖细胞的调节提供新的见解，而且有助于寻找改善老年人群海马神经发生的策略。