Hippocampal Subregion Transcriptomic Profiles Reflect Strategy Selection during Cognitive Aging

Abstract

Age-related cognitive impairments are associated with differentially expressed genes (DEGs) linked to defined neural systems; however, studies examining multiple regions of the hippocampus fail to find links between behavior and transcription in the dentate gyrus (DG). We hypothesized that use of a task requiring intact DG function would emphasize molecular signals in the DG associated with a decline in performance. We used a water maze beacon discrimination task to characterize young and middle-age male F344 rats, followed by a spatial reference memory probe trial test. Middle-age rats showed increased variability in discriminating two identical beacons. Use of an allocentric strategy and formation of a spatial reference memory were not different between age groups; however, older animals compensated for impaired beacon discrimination through greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions indicated DEGs in the DG of middle-age rats, linked to synaptic function and neurogenesis, correlated with beacon discrimination performance, suggesting that senescence of the DG underlies the impairment. Few genes correlated with spatial memory across age groups, with a greater number in region CA1. Age-related CA1 DEGs, correlated with spatial memory, were linked to regulation of neural activity. These results indicate that the beacon task is sensitive to impairment in middle age, and distinct gene profiles are observed in neural circuits that underlie beacon discrimination performance and allocentric memory. The use of different strategies in older animals and associated transcriptional profiles could provide an animal model for examining cognitive reserve and neural compensation of aging.

Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies

“…(Harrison et al, 2009;Berdugo-Vega et al, 2020). Pattern separation ↓ With age (Yassa and Stark, 2011;Holden and Gilbert, 2012;Gracian et al, 2013;Johnson et al, 2017;Ces et al, 2018;Smith et al, 2020).…”

“…• Age-related deficits may be related to altered synaptic plasticity and neurogenesis in the dentate gyrus (Wilson et al, 2006;Creer et al, 2010;Wu et al, 2015;Ces et al, 2018;Ray et al, 2018;Smith et al, 2020).…”

“…An age-related decline in the ability to distinguish objects as feature overlap increases or discriminate between the locations of two adjacent identical stimuli often referred to as pattern separation has been well documented in both humans (Yassa and Stark, 2011;Holden and Gilbert, 2012) and animal models (Gracian et al, 2013;Johnson et al, 2017;Ces et al, 2018;Smith et al, 2020). Experimental evidence supports a role for the dentate gyrus and CA3 subregions of the hippocampus in pattern separation (Wilson et al, 2006;Creer et al, 2010;Wu et al, 2015;Ces et al, 2018;Ray et al, 2018;Smith et al, 2020). Additionally, the dentate exhibits early markers of aging including altered synaptic plasticity and a decline in neurogenesis.…”

“…Maintenance of immune, synaptic, cholesterol/lipid metabolism pathways (Burger, 2010;Smith et al, 2020). Cognitive reserve (adaptation/plasticity to maintain cognitive function in the presence of aging and pathology)…”

“…Cellular resilience Regulation of Ca 2+ homeostasis, inflammation, oxidative stress, cellular waste disposal pathways (Blalock et al, 2003;Neuner et al, 2016Neuner et al, , 2019aMattson and Arumugam, 2018;Foster, 2019;Smith et al, 2020).…”