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Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.

海马神经发生，模式分离

基本信息

批准号：
9280819
负责人：
ANDRE ANTONIO FENTON
金额：
$ 28.91万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2019-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus. The dentate gyrus has been proposed to play a role in pattern separation, a process by which similar experiences or events are transformed into discrete non-overlapping representations (Leutgeb et al., 2007; Treves et al., 2008). Recent studies have found pattern separation deficits in humans during normal aging and in patients with Mild Cognitive Impairment (Toner et al., 2009; Yassa et al., 2011). We have shown that hippocampal neurogenesis is required for specific forms of learning such as context discrimination learning that may involve pattern separation (Sahay et al., 2011a). We are proposing to test the hypothesis that pharmacological strategies aimed at stimulating adult hippocampal neurogenesis, may have therapeutic potential for reversing impairments in pattern separation such as those seen during normal aging and in patients with Mild Cognitive Impairment. Specifically, we will use mice where the Bax pro-apoptotic gene has been deleted specifically from adult-born granule cells, as well as pharmacological strategies to increase neurogenesis in the dentate gyrus of aged mice and test whether such manipulations improve both cognitive discrimination and pattern separation.

描述（由申请人提供）：在哺乳动物成年大脑中，有两个区域，干细胞不断产生新的神经元，这一过程被称为神经发生：齿状回的室下区和颗粒下区。齿状回被认为在模式分离中发挥作用，模式分离是相似的经历或事件转化为离散的非重叠表征的过程（Leutgeb 等，2007；Treves 等，2008）。最近的研究发现，正常衰老过程中的人类和轻度认知障碍患者存在模式分离缺陷（Toner 等，2009；Yassa 等，2011）。我们已经证明，海马神经发生是特定形式的学习所必需的，例如可能涉及模式分离的情境辨别学习（Sahay et al., 2011a）。我们提议检验这样的假设：旨在刺激成人海马神经发生的药理学策略可能具有逆转模式分离损伤的治疗潜力，例如正常衰老过程中和轻度认知障碍患者中出现的损伤。具体来说，我们将使用从成年颗粒细胞中专门删除了 Bax 促凋亡基因的小鼠，以及增加老年小鼠齿状回神经发生的药理学策略，并测试这种操作是否可以改善认知辨别和模式分离。