Decoding the Neuronal Networks RejuvenatingHippocampal Cognitive Function

申请人发现细胞内在的、基因驱动的神经干细胞扩张和增加的神经发生通过促进灵活的上下文学习、异中心导航和记忆来恢复海马功能。这是一个基本的发现，表明认知能力的下降可以在老年时得到挽救或在一生中得到补偿。然而，这一发现的质量是现象学的，因为没有提供关于新神经元的添加如何触发观察到的认知表现改善的知识。一方面，很明显，新生神经元数量的增加一定在某种程度上改变了回路、神经元连接、活动和整体海马功能，但关于这些变化究竟是什么，以及为什么这些变化改善了而不是损害了功能，我们仍然完全缺乏知识。这不是一个微不足道的问题，因为对神经元数量的人为操纵很容易导致相反的结果，即大脑功能缺陷。值得注意的是，尽管在过去的50年里关于海马神经发生产生了大量的知识，但神经发生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的学习和记忆。如果成功，该项目将开启更雄心勃勃的目标，其长期愿景是开发和激活足以挽救认知障碍的神经元回路，而无需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.