Regulators of thyroid hormone action on adult hippocampal neurogenesis

海马颗粒下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，因为海马神经发生的缺陷可以清楚地与人类和动物模型的学习和记忆障碍有关。成年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，以形成功能性颗粒细胞神经元，并受多种内在和外在信号线索的支配。在后者中，甲状腺激素（TH）已被证明在动物模型中调节成年海马体中神经原性程序的后期阶段，人类甲状腺功能减退症与海马体神经发生相关的学习和记忆缺陷有关。然而，只有稀疏的信息可用于祖细胞阶段特异性表达和TH信号的各种组件的功能。在这里，我将阐明这些组件的详细表达在不同阶段的海马神经原性程序在体内和体外，并确定那些响应循环TH水平的变化，在小鼠模型的甲状腺功能减退和亢进。随后，我将研究在体内相关的TH信号调节参与的过程中，通过分析海马神经发生在适当的敲除动物，使用免疫组织化学和mRNA分析技术。鉴于它们的学习缺陷以及海马的形态学改变，缺乏TH转运蛋白Mct 8和Oatp 1c 1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，我将进一步产生和分析小鼠突变体，这些突变体特异性地在海马谱系中具有TH信号传导成分的缺失。总之，我的研究结果不仅将提供新的见解TH依赖性调节的神经干细胞和祖细胞在海马，但也有助于寻找策略，以改善老年人群海马神经发生。

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.