Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats
Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats
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DOI：
10.1101/lm.1172609
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发表时间：
2009-02-01
影响因子：
2
通讯作者：
Gage, Fred H.
中科院分区：
文献类型：
--
作者：
Jessberger, Sebastian;Clark, Robert E.;Gage, Fred H.
新的颗粒细胞在整个生命过程中都会在海马结构的齿状回中诞生。鉴于海马体在某些形式的学习和记忆过程中的基本作用，人们推测新生颗粒细胞有助于认知。然而，之前旨在将新生神经元与海马功能因果联系起来的策略使用的消融策略并非海马独有的，或者与炎症等实质性副作用相关。我们在这里使用慢病毒方法，通过使用显性失活 WNT (dnWNT) 抑制 WNT 信号传导来特异性阻断成年雄性大鼠齿状回的神经发生，WNT 信号传导在新生神经元的生成中至关重要。我们发现，在水迷宫任务中，成年神经发生对空间记忆的长期保留存在水平依赖性影响，因为与对照大鼠相比，新生神经元水平显着降低的大鼠在采集后> 2周的探测试验中表现出对目标区域的偏好较低。此外，神经发生水平严重降低的动物在依赖海马体的物体识别任务中受到损害。食物偏好的社会传播是一种也依赖于海马功能的行为测试，不受神经发生抑制的影响。在这里，我们确定了新生神经元在海马功能不同方面的作用，这将为使用实验和计算策略进一步阐明新生神经元影响行为的机制奠定基础。
New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials > 2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.