Age Impacts the Burden That Reference Memory Imparts on an Increasing Working Memory Load and Modifies Relationships With Cholinergic Activity

Abstract

Rodent aging research often utilizes spatial mazes, such as the water radial-arm-maze (WRAM), to evaluate cognition. The WRAM can simultaneously measure spatial working and reference memory, wherein these two memory types are often represented as orthogonal. There is evidence, however, that these two memory forms yield interference at a high working memory load. The current study systematically evaluated whether the presence of a reference memory component impacts handling of an increasing working memory load. Young and aged female rats were tested to assess whether aging impacts this relationship. Cholinergic projections from the basal forebrain to the hippocampus and cortex can affect cognitive outcomes, and are negatively impacted by aging. To evaluate whether age-related changes in working and reference memory profiles are associated with cholinergic functioning, we assessed choline acetyltransferase activity in these behaviorally-tested rats. Results showed that young rats outperformed aged rats on a task testing solely working memory. The addition of a reference memory component deteriorated the ability to handle an increasing working memory load, such that young rats performed similar to their aged counterparts. Aged rats also had challenges when reference memory was present, but in a different context. Specifically, aged rats had difficulty remembering which reference memory arms they had entered within a session, compared to young rats. Further, aged rats that excelled in reference memory also excelled in working memory when working memory demand was high, a relationship not seen in young rats. Relationships between cholinergic activity and maze performance differed by age in direction and brain region, reflecting the complex role that the cholinergic system plays in memory and attentional processes across the female lifespan. Overall, the addition of a reference memory requirement detrimentally impacted the ability to handle working memory information across young and aged timepoints, especially when the working memory challenge was high; these age-related deficits manifested differently with the addition of a reference memory component. This interplay between working and reference memory provides insight into the multiple domains necessary to solve complex cognitive tasks, potentially improving the understanding of complexities of age- and disease- related memory failures and optimizing their respective treatments.

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

“…We also note here that MWM outcomes are different from the pattern of effects observed for RM outcomes on the WRAM. This coincides with several studies from our laboratory indicating that assessing reference memory in conjunction with working memory differs from assessments of one memory type alone, effects seen in both young and aged females 35 , 40 , 55 .…”

Clinically Used Hormone Formulations Differentially Impact Memory, Anxiety-Like, and Depressive-Like Behaviors in a Rat Model of Transitional Menopause

“…Rats that received E2 plus levonorgestrel treatment also had improved reference memory during task acquisition compared to rats treated with E2 plus progesterone concomitantly, suggesting a unique cognitively beneficial role for levonorgestrel when combined with E2 to enhance learning on a complex spatial working memory task. Reference memory benefits observed for the rats treated with daily E2 plus levonorgestrel treatment did not carry over into MM, indicating that the presence of a working memory component in a task alters outcomes on the reference memory measure, an effect we have previously shown in normally aging, ovary-intact rats without hormone treatment ( Bernaud et al, 2021 ). During the latter portion of WRAM testing, transitionally menopausal rats treated with only progesterone showed working memory impairments when working memory was taxed compared to counterparts without hormone treatment, with levonorgestrel treatment, or with E2 plus progesterone treatment.…”

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“…Day 1 was considered task acquisition and was not included in the analyses. Based on previous findings from our laboratory, WRAM data were blocked into the Learning Phase (Days 2-8) and the Asymptotic Phase (Days 9-12), as published previously ( Bimonte and Denenberg, 1999 ; Bimonte-Nelson et al., 2003a ; Bimonte-Nelson et al., 2003a ; Bimonte-Nelson et al., 2004 ; Mennenga et al., 2015a ; Braden et al., 2017 ; Koebele et al., 2020a ; Bernaud et al., 2021 ). A priori planned analyses evaluating high working memory load trials (Trial 3 and Trial 4) were also completed, as our laboratory has previously reported age- and hormone- mediated effects when working memory load is sufficiently burdened ( Bimonte and Denenberg, 1999 ; Mennenga et al., 2015a ; Mennenga et al., 2015b ; Koebele et al., 2019 ; Koebele et al., 2020b ).…”