Decoding the Neuronal Networks RejuvenatingHippocampal Cognitive Function

申请人已经发现，神经干细胞的细胞内在的、遗传驱动的扩增和增加的神经发生通过促进灵活的情境学习、非中心导航和记忆来恢复海马功能。这是一个基本的发现，表明认知能力下降可以在老年得到挽救或在整个生命中得到补偿。然而，这一发现的质量是现象学的，因为没有提供关于新生神经元的添加如何引发所观察到的认知表现的改善的知识。一方面，很明显，增加新生神经元的数量一定以某种方式改变了电路，神经元连接，活动和整体海马功能，但对于这些变化究竟是什么以及为什么这些变化改善而不是损害功能，仍然绝对缺乏知识。这不是一个微不足道的问题，因为人工操纵神经元数量很容易导致相反的结果，导致大脑功能缺陷。值得注意的是，尽管在过去的50年中产生了大量的知识海马神经发生，神经发生的增加可能促进学习或记忆表现的电生理机制仍然未知。这项应用的挑战性目标是填补这一知识空白，其雄心勃勃的目标是解释新生神经元的数量如何影响海马体的学习和记忆。如果成功的话，这个项目将开启一个更加雄心勃勃的目标，即利用和激活神经元回路，这些神经元回路被发现足以挽救认知障碍，而不需要使用目前无法转化为人类的实验方法和操作。

The applicant has found that a cell-intrinsic, genetically-driven expansion of neural stem cells and increased neurogenesis rejuvenated hippocampal function by promoting flexible contextual learning, allocentric navigation and memory. This is a fundamental finding showing that cognitive decline can be rescued in old age or compensated throughout life. Yet, the quality of this finding is phenomenological in the sense that no knowledge is provided with regard to how an addition of newborn neurons could have triggered the observed improvements in cognitive performance. On the one hand, it is clear that increasing the number of newborn neurons must in some way have changed circuitry, neuronal connectivity, activity and overall hippocampal function but an absolute lack of knowledge remains with regard to what exactly these changes are and why have these improved, rather than impaired, function. This is no trivial question because an artificial manipulation of neuron number could easily have led to the opposite outcome with defects in brain function. Remarkably, and despite the great bulk of knowledge generated in the last 50 years on hippocampal neurogenesis, the electrophysiological mechanisms by which an increase in neurogenesis may promote learning or memory performance remain unknown. The challenging goal of this application is to fill up this gap in knowledge with the ambitious aim to explain how the number of newborn neurons influences hippocampal learning and memory throughout life. If successful, this project will open up even more ambitious aims with the long-term vision to exploit and activate the neuronal circuits found to be sufficient to rescue cognitive impairment without the use of experimental methods and manipulations that are currently not translatable to humans.