Abstract
BACKGROUND: Aging is accompanied by a decline in memory but these alterations are extremely variable between subjects: some individuals preserve cognitive abilities (Resilient, Res), whereas others show a clear substantial cognitive decline incapacitating in everyday life (Vulnerable, Vul). These inter-individual differences have also been described in rodents especially in tasks measuring spatial memory abilities. We believe that understanding the processes underlying such individual differences is a key step to predict, prevent or slow age-related cognitive disorders. Spatial memory processes depend upon the hippocampus and more particularly upon the creation of new neurons in the dentate gyrus. Aging is associated with an exhaustion of the pool of new neurons and their delayed maturation. However, it remains unknown if aging influences the integration and role of adult-born hippocampal neurons (ABNs) generated early in adult life and whether this is influenced by the cognitive status of the individuals. AIMS & OBJECTIVES: Spatial memory processes depend upon the hippocampus and more particularly upon the creation of new neurons in the dentate gyrus. Aging is associated with an exhaustion of the pool of new neurons and their delayed maturation. However, it remains unknown if aging influences the integration and role of adult-born hippocampal neurons (ABNs) generated early in adult life and whether this is influenced by the cognitive status of the individuals. METHOD: To analyze the lifelong survival of ABNs born in young adult rats (3-month-old), animals were injected with thymidine analog (Bromodeoxyuridine (BrdU), intraperitoneal injections) that incorporated into dividing cells at the time of injection. To specifically study the morphological features of ABNs, Moloney leukemia virus-based retroviral vectors (M-rv) were injected in the dentate gyrus at the same period. Different M-rv were used to study the morphology (M-rv-GFP), glutamatergic post-synaptic density (M-rv-PSD95-GFP) and mitochondrial network (M-rv-MitoDsRed) of ABNs. To examine the progressive mechanisms underlying successful aging, we adopted a pseudo-longitudinal strategy in which rats were submitted to a spatial navigation learning task in the Morris watermaze either at the end of adulthood (8-month-old rats), middle-age (12-month-old rats) or old age (18-month-old rats). Within each of the 3 cohorts of rats, resilient and vulnerable animals were identified. Subsequently, the morphological analysis was performed in rats with the best memory abilities, and rats with the worst memory abilities. Using this strategy, ABNs aged either 5, 9 or 15 month-old in rats aged respectively 8, 12 and 18 month-old at the time of training and sacrifice were analyzed. RESULTS: We will show that long-lived ABNs support successful cognitive aging by preserving their synaptic inputs onto the proximal segments of their dendrites, and that these proximal synaptic sites also demonstrate a maintenance of their mitochondrial homeostasis. Furthermore, by-passing the reduced inputs of ABNs in vulnerable rats through direct optogenetic stimulation successfully improved their memory abilities. DISCUSSION & CONCLUSIONS: Overall, our data indicate not only the rate of neurogenesis but also the maintenance of long-lived ABNs integration within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.