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

描述(申请人提供)：在哺乳动物成年大脑中，干细胞不断地在两个区域产生新的神经元，这一过程被称为神经发生：齿状回的脑室下区和颗粒下区。齿状回被提出在模式分离中发挥作用，这是一个将相似的经历或事件转化为离散的非重叠表征的过程(Leutgeb等人，2007年；Treves等人，2008年)。最近的研究发现，人类在正常衰老和轻度认知障碍患者中存在模式分离缺陷(Toner等人，2009年；Yassa等人，2011年)。我们已经表明，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上下文辨别学习(Sahay等人，2011a)。我们建议测试这一假说，即旨在刺激成年海马神经发生的药物策略可能具有逆转模式分离障碍的治疗潜力，例如在正常衰老和轻度认知障碍患者中所见的障碍。具体地说，我们将使用成年出生的颗粒细胞中特定缺失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物策略，并测试这种操作是否既改善了认知辨别能力，又改善了模式分离。

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.