Running throughout middle-age keeps old adult-born neurons wired.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear if adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in 2-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing 'old' new neurons. We identified and quantified the direct afferent inputs to the adult-born neurons within the hippocampus and (sub)cortical areas. Here we show that long-term running substantially modifies the network of the neurons generated in young adult mice upon middle-age. Exercise increases input from hippocampal interneurons onto 'old' adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of 'old' new neurons, born during early adulthood, within a network that is important for memory function during aging. Significance statement Exercise benefits brain function, however, the underlying mechanisms remain unclear. We show that long-term running increases hippocampal neurogenesis, and modifies the network of new neurons that were born in young adult mice, in a manner that optimally supports memory function at middle age.