Intersection of active zone plasticity and memory formation in the aging mushroom body

Aging is accompanied by cognitive decline in a major segment of the population, with age-induced memory impairment (AMI) emerging as one of the top public health threats. At the same time, however, the aging of the brain has not been well understood at a molecular and cellular level. A fundamental challenge when studying cognitive aging is the differentiation between causative and correlative or even adaptive and protective changes. As a result of this, causal relations between molecular and cellular aspects of brain aging, on the one hand, and AMI, on the other hand, have hardly been established. This is also due to the aging process being subject to a complex interplay of regulatory and executive mechanisms.Activity-dependent synaptic plasticity is considered necessary and sufficient for the encoding and storage of memories across all animal model systems investigated. In fact, instead of emphasizing the loss of neurons, several studies in rodent models are now pointing towards rather subtle age-related synaptic alterations in the hippocampus and other parts of the cortical brain as being associated with AMI. Synapses, however, are complex “nanomachines” whose in vivo operational principles we are just beginning to understand. Causal connections between age-associated synaptic changes and AMI have not been systematically achieved. In this grant, I formulate a novel "multiscale" approach, which will help to close this gap by connecting directly between the functional and structural status of memory-relevant synapses with the behavioral level, and this across the lifetime of our model. We start from a unique set of findings and tools enabling us to connect molecular synaptic phenomena with AMI directly.