Identification and regulation of neural stem cells in the adult mammalian hypothalamus

成年哺乳动物神经干细胞(NSCs)为中枢神经系统的可塑性提供了惊人的证据，并为神经系统疾病的细胞替代治疗开辟了新的可能性。目前还没有确凿的证据表明，在成人下丘脑中存在神经干细胞，而下丘脑是许多重要行为的必要区域，这些行为对生存至关重要。这项提议的目的是在成年哺乳动物下丘脑中鉴定一种新的神经干细胞群体。我们发现，在成年小鼠的下丘脑中，有一小部分细胞表达核受体蛋白TLX，并在体内暴露于生长因子时能长出新的神经元。这有力地表明TLX表达细胞是成人下丘脑新神经元的来源。我们将首先分析这些表达TLX的细胞的微环境，并将使用已建立的动物模型来研究它们产生不同神经元亚型的潜力。作为成年小鼠大脑中的神经干细胞决定因素，TLX的作用将通过增益或损失函数进行进一步分析。将探讨下丘脑NSCs在衰老和脑损伤过程中的变化和作用。本项目所获得的结果和基因工具将为在体内研究成人下丘脑神经干细胞奠定基础，这将大大增加研究下丘脑成人神经发生意义的可行性。从而为理解许多与下丘脑调节失调有关的疾病提供了新的见解，如肥胖和攻击性。

Adult mammalian neural stem cells (NSCs) provide striking evidence of plasticity of the central nervous system and open up a new possibility for cell replacement therapy for neurological disorders. No solid evidence has been demonstrated for the existence of NSCs in the adult hypothalamus, which is an essential region for many important behaviors that are essential for survival. This proposal aims to identify a novel neural stem cell population in the adult mammalian hypothalamus. We found that in the adult mouse hypothalamus there is a small population of cells, which expresses the nuclear receptor protein Tlx and can give rise to new neurons when exposed to growth factors in vivo. This strongly suggests that the Tlx expressing cells are the origin of new neurons in the adult hypothalamus. We will first analyze the microenvironment of these Tlx expressing cells and their potential to generate different neuronal subtypes will be investigated using the established animal models. As a NSCs determinant in the adult mouse brain, the role of Tlx will be further analyzed using gain or loss-off function. Changes and contribution of the hypothalamic NSCs during aging and brain injury will be investigated. The results and genetic tools obtained from the proposed projects will settle the basis for studying the adult hypothalamic NSCs in vivo, which will greatly increase the feasibility to investigate the significance of hypothalamic adult neurogenesis. Thus provide new insights in understanding many diseases which are related to hypothalamus dysregulation, such as obesity and aggression.