Long-Run Olfactory Enrichment Promotes Non-Olfactory Cognition, Noradrenergic Plasticity And Remodeling Of Brain Functional Connectivity In Aged Mice

ABSTRACT Normal brain aging is accompanied by functional and structural changes, leading to cognitive decline. A high level of cognitive stimulation during life is associated with improved cognitive performances in elderly, forming the so-called cognitive reserve whose cellular mechanisms remain largely unknown. Noradrenaline has been proposed as a molecular link between environmental stimulation and the constitution of the cognitive reserve. Taking advantage of the ability of olfactory stimulation to trigger noradrenaline release, we used repeated olfactory enrichment sessions distributed over the mouse lifespan to enable the cognitive reserve buildup. Mice submitted to lifelong olfactory enrichment whether started in early or late adulthood, displayed improved olfactory discrimination at late ages. Interestingly, benefits extended to spatial memory and cognitive flexibility and olfactory and non-olfactory cognitive performances correlated with increased noradrenergic innervation in the olfactory bulb and dorsal hippocampus. Finally, using c-Fos mapping and connectivity analysis, we reported task-specific remodeling of functional neural networks in aged mice with increased network specialization or enlargement in an olfactory discrimination or a spatial memory task respectively. We thus propose long-run olfactory enrichment as a mouse model of the cognitive reserve buildup relying on plasticity of the noradrenergic system and network remodeling to promote better cognitive aging.