Angiogenic determinants of endogenous adult neurogenesis

描述(申请人提供)：成人发声控制核团HVC 鸣禽一生中从附近的脑室区域产生新的神经元 祖细胞。这些神经元的招募和存活受 性腺类固醇、睾酮和雌二醇。然而，内皮细胞分裂 在成人HVC中发现的第一个细胞反应是在睾丸素之后 给药，先于雄激素相关的神经胶质发生和神经元 招募时间超过一周。我们已经发现，睾丸素能迅速诱导 血管内皮生长因子及其受体的产生 HVC中VEGF-R2/KDR的表达。这导致了内皮细胞的分裂，它预计 下腔静脉微血管的局部局限性扩张。被激活的 然后内皮细胞产生神经营养因子BDNF，这已被证明是 支持哺乳动物和鸟类的神经元募集 脑室区，其诱导与新的 神经元连接到HVC。 性腺类固醇诱导的内皮和基质释放的细胞因子可能因此 对成人大脑中的神经元招募有重要贡献。在这 竞争性更新应用，我们假设性腺类固醇诱导 血管生成可能是成年HVC神经元增加的关键，而且 血管生成可能为神经元提供必要的许可条件 向成人脑实质募集。为了更好地理解允许的 新神经元整合到成人大脑的条件，我们建议 问以下问题： 1)性腺激素对血管内皮生长因子及其受体的诱导作用 睾酮诱导成人HVC血管生成所必需的是 睾酮介导的神经元所必需的类固醇诱导的血管生成 招聘？抑制血管生成是否会消除神经元的增加 HVC？3)局部血管生成是否足以指导神经细胞从 神经源性上皮？新的神经元选择性地迁移到HVC是因为它的 性腺激素激活后脑源性神经营养因子水平升高？4)激素激活 基质金属蛋白酶对神经元加成有重要作用？那么，基质金属蛋白酶呢？ 抑制抑制招募？ 这些实验询问成年HVC中的神经发生是否依赖于前驱因素 局部血管生成。他们试图定义哪些是必要的和充分的 可能由类固醇激活提供的神经元募集条件 内皮细胞。通过这样做，他们扩展了我们对许可的理解 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，并被其他非神经性来源的人接受 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.