Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis

Abstract

Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience. This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies. Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training. Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility. These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.

ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

“…We produced a dataset of conditioned fear memory (GN trait ID: 5XF_10474) with 14 month old B-BXD animals from 42 different strains ( Figure 5A ). At this age, PGBs are present in the B6 hippocampus and age-related behavioral alterations such as reduced CFM become apparent (Amelchenko et al, 2023; Hamieh et al, 2021; Jucker et al, 1992; Wu et al, 2015). Importantly, no correlation was found between CFM (time spent frozen) and PGB density in the subset of overlapping strains ( n = 13) ( Figure 5B,C ).…”

“…To mitigate this limitation, we performed conditioned fear memory (CFM) tests on aged B-BXDs, which again yielded no evidence suggesting negative effects of PGBs on cognition. Studies have shown that CFM is a effective readout of hippocampal function in spatial memory and learning confidence (Amelchenko et al, 2023; Hernández-Mercado and Zepeda, 2022) and have been demonstrated to deliver readable outcomes in cognitive performance tests in an age related context (Hamieh et al, 2021; Hernández-Mercado and Zepeda, 2022; Verbitsky et al, 2004; Wu et al, 2015). Although we cannot exclude an effect of PGBs on cognition at geriatric stages, we conclude it is unlikely that age-related PGB burden in the hippocampus has a strong negative effect on cognitive function up to 18-months of age.…”