Aging is an inevitable and complex biological phenomenon associated with a progressive decline of sensory, motor and cognitive functions with time, affecting quality of life and health. Apart from any age-related neurodegenerative diseases, brain aging is accompanied by functional and structural changes, including brain networks’ remodeling (Damoiseaux, 2017) and alterations in synaptic function (van der Zee, 2015). A potentially powerful tool to achieve successful brain aging is to boost the cognitive reserve. This concept was initially proposed to explain the discrepancy between considerable histological brain alterations and relatively preserved cognitive performances in some Alzheimer's patients and has been extended to normal aging (Barulli and Stern, 2013, Cabeza et al., 2018, Grady, 2012, Reuter-Lorenz and Park, 2014, Stern et al., 2019). Epidemiological studies indicate that a high level of brain stimulation through education, occupational attainment or social activities, is associated with changes in neural activity and connectivity possibly supporting better capacity or adaptability of neural networks in humans. These observations prompted the development of training strategies in the auditory system, with positive outcomes on performances and remodeling of brain activation in older subjects (e.g. Holman and de Villers-Sidani, 2014).

Despite a growing interest toward the cognitive reserve, the mechanisms underlying the implementation of various experiences into brain networks to allow better performances during the cognitive reserve buildup remain mostly unknown. The noradrenergic theory of the cognitive reserve proposes the neuromodulator noradrenaline (NA) as a key player in this process (Clewett et al., 2016, Mather and Harley, 2016, Robertson, 2013). This hypothesis arose from several clinical and experimental observations. The Locus Coeruleus (the main source of cortical NA) is vulnerable to aging and its anatomical integrity is positively associated with preserved cognitive functions in healthy humans (e.g. Clewett et al., 2016; Dahl et al., 2019; Langley et al., 2020; Plini et al., 2021; Wilson et al., 2013). NA is released widely in cortical areas and participates in the modulation of sensory processing and many cognitive functions, such as attention, flexibility and memory (Borodovitsyna et al., 2017, Breton-Provencher et al., 2021, Poe et al., 2020, Sara, 2009, Sara and Bouret, 2012). The activation of the Locus Coeruleus is sensitive to novel and salient sensory stimuli (Berridge and Waterhouse, 2003). In the hippocampus, NA release can be induced by environmental enrichment (Brenes et al., 2009, Galani et al., 2007) and may contribute to spatial memory by enhancing long-term synaptic plasticity (Li et al., 2013). All these properties of the noradrenergic system suggest that soliciting this neuromodulatory system could be an effective strategy to promote better cognitive aging.

Our group previously reported that 30-40 days of olfactory enrichment (exposure to a new odor every day) is activating the noradrenergic system, inducing NA release and improving olfactory discrimination and memory in young adult mice (Rey et al., 2012, Veyrac et al., 2009). In contrast, it has no such effect on olfactory memory in older mice (Rey et al., 2012). The aim of the current study was to determine the effects of a long-term olfactory enrichment that was repeated during the lifespan, on olfactory and cognitive functions, brain activation and connectivity, and the state of the noradrenergic system in older mice. Based on the literature, we hypothesized that lifelong olfactory enrichment sessions would allow repeated activation of the noradrenergic system and improve not only olfactory perception but also cognition at late ages. We also assessed whether long-term olfactory enrichment would be efficient when started late in life. For that purpose, we implemented olfactory enrichment sessions, starting in young adulthood (2 months) or at middle age (12 months) and that were repeated along the lifespan of the mice. We performed a longitudinal follow up, from young adulthood to 18 months, of olfactory performances, spatial memory and cognitive flexibility, as these are known to be age-sensitive cognitive functions (e.g. Roman et al., 1996; Barense, 2002; Schoenbaum et al., 2006; Murai et al., 2007; Brushfield et al., 2008; Wimmer et al., 2012). We then investigated the integrity of the Locus Coeruleus and the density of NA innervation in brain regions related to the assessed behavioral performances. Last, we characterized brain activation and functional connectivity through c-Fos mapping, to identify network remodeling associated to the cognitive performances.