Angiogenic determinants of endogenous adult neurogenesis

描述（申请人提供）：成人发声控制核团HVC 鸣禽一生都从邻近的心室区产生新的神经元 祖细胞这些神经元的募集和存活受到 性腺类固醇睾酮和雌二醇然而内皮细胞分裂 是睾酮治疗后成人HVC中观察到的第一个细胞反应 施用，并且先于雄激素相关的胶质细胞生成和神经元生成。 招聘时间超过一周我们发现睾丸激素能迅速诱导 血管内皮生长因子（VEGF）及其受体的产生 HVC中的VEGF-R2/KDR。这导致内皮细胞分裂， HVC微血管的局部受限扩张。活性 然后内皮细胞产生神经营养因子BDNF，已经证明BDNF 支持哺乳动物和鸟类的神经元募集 心室区，其诱导与招募新的 神经元到HVC。 性腺激素诱导的内皮细胞和基质释放的细胞因子可能因此 对成人大脑中神经元的募集有重要作用。在这 竞争性更新的应用，我们假设，性腺类固醇诱导 血管生成可能是神经元添加到成人HVC的关键， 血管生成可以为神经元的生长提供必要的容许条件。 募集到成人脑实质中。为了更好地理解 新的神经元整合到成人大脑的条件，我们建议， 问以下问题： 1)是性腺激素相关的诱导VEGF及其受体 是睾丸激素诱导成人HVC血管生成所必需的吗？2)是 睾酮介导神经元血管生成所必需的类固醇诱导的血管生成 招募？血管生成的抑制是否消除了神经元的添加， HVC？3)局部血管生成是否足以指导神经元从 神经原上皮新的神经元迁移到HVC是因为它的 性腺类固醇激活后BDNF水平升高4)做类固醇激活 基质金属蛋白酶对神经元加法有重要贡献？MMP是否 抑制抑制募集？ 这些实验询问成人HVC的神经发生是否依赖于前因， 局部血管生成。他们试图定义那些必要的和充分的 神经元募集的条件，可由类固醇激活的 内皮细胞通过这样做，他们扩展了我们对宽容的理解， 成人大脑中神经发生的条件，并可能告诉我们如何 诱导神经元募集到其他非神经源性 成人大脑的区域。

DESCRIPTION (provided by applicant): The vocal control nucleus HVC of adult songbirds generates new neurons throughout life from nearby ventricular zone progenitor cells. The recruitment and survival of these neurons is modulated by the gonadal steroids testosterone and estradiol. Yet endothelial cell division is the first cellular response noted in the adult HVC after testosterone administration, and precedes androgen-associated gliogenesis and neuronal recruitment by over a week. We have found that testosterone rapidly induces the production of both vascular endothelial growth factor (VEGF) and its receptor VEGF-R2/KDR in HVC. This leads to endothelial division, which anticipates the regionally-restricted expansion of the HVC microvasculature. The activated endothelial cells then produce the neurotrophin BDNF, which has been shown to support neuronal recruitment from the mammalian as well as the avian ventricular zone, and whose induction is associated with the recruitment of new neurons to HVC. Gonadal steroid-induced endothelial and matrix-released cytokines may thereby contribute importantly to neuronal recruitment in the adult brain. In this competitive renewal application, we postulate that gonadal steroid-induced angiogenesis may be critical to neuronal addition to the adult HVC, and that angiogenesis may provide necessary permissive conditions for neuronal recruitment into adult brain parenchyma. To better understand the permissive conditions for the integration of new neurons into adult brain, we propose to ask the following: 1) Is the gonadal steroid-associated induction of VEGF and its receptor necessary for testosterone-induced angiogenesis in the adult HVC? 2) Is steroid-induced angiogenesis necessary for testosterone-mediated neuronal recruitment? Does the suppression of angiogenesis abrogate neuronal addition to HVC? 3) Is local angiogenesis sufficient to direct neuronal recruitment from a neurogenic epithelium? Do new neurons migrate selectively to HVC because of its high BDNF levels after gonadal steroid activation? 4) Do steroid-activated matrix metalloproteinases contribute importantly to neuronal addition? Does MMP inhibition suppress recruitment? These experiments ask if neurogenesis in the adult HVC depends upon antecedent local angiogenesis. They seek to define those necessary and sufficient conditions for neuronal recruitment that may be provided by steroid-activated endothelial cells. By so doing, they extend our understanding of the permissive conditions for neurogenesis in the adult brain, and may inform us as to how to induce neuronal recruitment to, and acceptance by, otherwise non-neurogenic regions of the adult brain.