Decoding the Neuronal Networks RejuvenatingHippocampal Cognitive Function

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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.