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

海马神经发生，模式分离

• 批准号: 9067887
• 负责人: ANDRE ANTONIO FENTON
• 金额: $ 32.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067887
• 关键词: Ablation; Action Potentials; Adult; Age; Age-Months; Age-associated memory impairment; Apoptotic; Behavioral Paradigm; Brain; Breeding; Cells; Chronic; Discrimination; Discrimination Learning; Electrophysiology (science); Event; Exercise; Fluoxetine; Fright; Genes; Genetic; Halorhodopsins; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Learning; Measures; Mediating; Memory impairment; Mus; Neurons; Patients; Pattern; Play; Process; Regimen; Role; Stem cells; Tamoxifen; Testing; Therapeutic; age related; aged; cohort; critical period; dentate gyrus; experience; genetic manipulation; granule cell; improved; mild cognitive impairment; neurogenesis; neuromechanism; normal aging; object recognition; progenitor; research study; subventricular zone; young adult

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）：在哺乳动物的成年大脑中，在两个区域中，干细胞不断引起新的神经元，这是一种称为神经发生的过程：脑室下区域和齿状回的下粒区。已经提出了齿状回在模式分离中发挥作用，该过程通过将类似的经验或事件转化为离散的非重叠表示形式（Leutgeb等，2007； Treves等，2008）。最近的研究发现，正常衰老和轻度认知障碍的患者在人类中的模式分离缺陷（Toner等，2009； Yassa等，2011）。我们已经表明，特定形式的学习形式需要海马神经发生，例如上下文歧视学习可能涉及模式分离（Sahay等，2011a）。我们提出要检验以下假设：旨在刺激成年海马神经发生的药理学策略可能具有逆转模式分离损害的治疗潜力，例如正常衰老期间和轻度认知障碍患者。具体而言，我们将使用小鼠在成年出生的颗粒细胞中特异性删除Bax促凋亡基因的情况，以及药理学策略，以增加老年小鼠齿状回的神经发生并测试此类操作是否可以改善认知歧视和模式分离。