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



doi: 10.3389/fnbeh.2021.610078.


eCollection 2021.

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Victoria E Bernaud et al.


Front Behav Neurosci.


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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.


Keywords:

aging; attention; cholinergic system; female; rat; reference memory; water radial-arm maze; working memory.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures


Figure 1



Figure 1

Study timeline and WRAM configurations. (A) The study timeline depicts the age at arrival and the commencement of behavioral testing, including WRAM and VP. (B) The 8-Arm WRAM apparatus, with seven of the eight arms platformed. Besides the starting arm, all other arms in the 8-Arm WRAM are spatial working memory arms. (C) The 12-Arm WRAM apparatus, with seven of the 12 arms platformed, making for a total of seven working memory arms, like that of the 8-Arm WRAM. This maze, however, has five reference memory arms, allowing for the analysis of both spatial reference and working memory performance on the WRAM.


Figure 2



Figure 2

WRAM performance represented as WMC errors and their contribution to Total errors. The proportion of Total errors (±SEM) comprised of WMC errors for both mazes across Acquisition and Asymptotic Phases of testing. For the 8-Arm WRAM, other than start arm errors, all errors must be WMC errors; however, in the 12-Arm WRAM, rats can make WMC errors, as well as RM and WMI errors. While the rats tested on the 8-Arm WRAM rarely made entries into the only arm without a platform i.e., the start arm, rats tested on the 12-Arm WRAM made a large number of unplatformed arm entries. This further demonstrates the separation of errors made when a reference memory component is added to the working memory portion of the WRAM.


Figure 3



Figure 3

WMC errors during the Acquisition Phase of WRAM testing. (A) WMC errors for the Acquisition Phase of WRAM testing (Days 2–7). With an effect of Maze and an Age × Maze Interaction, it was found that within the 8-Arm WRAM there was an effect of Age, but not for the 12-Arm WRAM; additionally, young rats tested on the 8-Arm WRAM performed better than those tested on the 12-Arm WRAM, but performance across maze did not differ for aged rats. (B) Working memory performance as measured by WMC errors made across all testing trials (Trials 2–7). At the highest working memory load (Trial 7), there was an Age × Maze interaction, where aged rats performing on the 8-Arm WRAM made more errors than their younger counterparts, and the rats performing on the 12-Arm WRAM did not differ by age. Additionally, for young rats there was an effect of Maze, where rats tested on the 8-Arm WRAM made fewer errors than their counterparts tested on the 12-Arm WRAM, with no effect amongst aged rats.


Figure 4



Figure 4

WMC errors during the Asymptotic Phase of WRAM testing. (A) WMC errors for the Asymptotic Phase of WRAM testing (Days 8–12). With an effect of Maze and an effect of Age, it was found that within the 8-Arm WRAM there was an effect of Age, but not for the 12-Arm WRAM; notably distinct from the Acquisition Phase, both young and aged rats tested on the 8-Arm WRAM performed better their counterparts tested on the 12-Arm WRAM. (B) Working memory performance as assessed via WMC errors made across all testing trials (Trials 2–7). At the highest working memory load (Trial 7), there was a main effect of Maze and a main effect of Age, where aged rats performing on the 8-Arm WRAM made more errors than their younger counterparts, and the rats performing on the 12-Arm WRAM did not differ by age. Additionally, there was an effect of Maze for young rats exclusively, where young rat performance on the 8-Arm WRAM was better than that of the 12-Arm WRAM, with no effect of Maze for aged rats.


Figure 5



Figure 5

WMI errors within the 12-Arm WRAM. (A) The marginal main effect of Age on WMI errors within the 12-Arm WRAM for the Acquisition Phase (Days 2–7), where aged rats made marginally more WMI errors than young rats. (B) WMI errors across Trials 1–7 for Acquisition Phase (Days 2–7) of testing. (C) The main effect of Age on WMI errors within the 12-Arm WRAM for the Asymptotic Phase of testing (Days 8–12), where aged rats made significantly more WMI errors than young rats. (D) WMI errors across Trials 1–7 for the Asymptotic Phase (Days 8–12) of testing. For the Acquisition Phase, age effects were particular to a high working memory load trial, whereas by the end of testing, in the Asymptotic Phase, the age effects were not trial-dependent.


Figure 6



Figure 6

Correlations between RM and WMC errors on the WRAM. A significant positive correlation was found between RM errors made on an early trial (Trial 2), with a relatively low cognitive load, and WMC errors made on the last trial (Trial 7), or the highest cognitive load trial, for aged rats performing on the 12-Arm WRAM on the last day of testing, but not for young rats [R2 = 0.53, r(8) = 0.73, *p < 0.05]. Several rats in the aged group made the same number of RM and WMC errors for this figure, resulting in the overlap of data points represented.


Figure 7



Figure 7

Performance on the Visible Platform (VP) task. Latency (in seconds) across Trials 1–6 on the VP task, where groups did not differ in ability to perform the procedural components of a water escape task.


Figure 8



Figure 8

ChAT activity in various brain regions, and correlations with WRAM performance. (A) Average ChAT activity levels in the ventral hippocampus, where aged rats had greater ChAT activity. (B) Average ChAT activity levels in the frontal cortex, where aged rats had greater ChAT activity. (C) A significant positive correlation was found between ChAT activity in the ventral hippocampus and WMC errors made during the Asymptotic Phase for aged rats performing on the 8-Arm WRAM specifically [R2 = 0.70, r(7) = 0.84, **p < 0.01). (D) A significant negative correlation was found between ChAT activity in the frontal cortex and WMC errors made during the Asymptotic Phase for young rats tested on the 8-Arm WRAM [R2 = 0.61, r(8) = −0.78, **p < 0.01].

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