Distinct manifestations of executive dysfunction in aged rats

Abstract

Different components of executive function such as working memory, attention, and cognitive flexibility can be dissociated behaviorally and mechanistically; however, the within-subject influences of normal aging on different aspects of executive function remain ill-defined. To better define these relationships, young adult and aged male F344 rats were cross-characterized on an attentional set-shifting task that assesses cognitive flexibility and a delayed response task that assesses working memory. Across tasks, aged rats were impaired relative to young; however, there was significant variability in individual performance within the aged cohort. Notably, performance on the set-shifting task and performance at long delays on the delayed response task were inversely related among aged rats. Additional experiments showed no relationship between aged rats' performance on the set-shifting task and performance on a hippocampal-dependent spatial reference memory task. These data indicate that normal aging can produce distinct manifestations of executive dysfunction, and support the need to better understand the unique mechanisms contributing to different forms of prefrontal cortical-supported executive decline across the lifespan.

Figure 1. Schematics of the set-shifting and working memory tasks

A) Schematic of the set-shifting task. Rats were initially trained in a visual discrimination in which they had to press the response lever illuminated by a small lamp, irrespective of its left/right location. Upon reaching criterion performance, they were shifted to a left/right discrimination in which they had to press the response lever in a particular location, irrespective of whether that lever was illuminated by the lamp. B) Schematic of the delayed response working memory task. Rats had to press a lever when extended during the sample phase, then, after a variable delay, press that same lever during the choice phase to earn a food reward.

Figure 2. Performance of young and aged rats on the set-shifting task

A) Aged rats were no different from young in the number of trials required to reach criterion performance on the initial visual discrimination. B) In contrast, following the set-shift, aged rats took significantly more trials to reach criterion performance on the left/right discrimination. C) Aged rats made significanly more total errors than young in reaching criterion performance on the set-shift. The majority of these errors involved responding according to the previously-reinforced (visual discrimination) response rule (e.g., if the left lever were correct during the left/right discrimination, a “previously-reinforced” error would involve responding on the right lever on trials on which the right lever was illuminated), and aged rats made significantly more previously-reinforced errors than young. In contrast, there were many fewer errors of the “never-reinforced” type (e.g., in the previous example, responding on the right lever on trials on which the left lever was illuminated), and these did not differ between young and aged rats. * p < 0.05.

Figure 3. Variability among aged rats on the set-shifting task

A) There was significantly greater variability in the number of trials to criterion on the set-shift among aged compared to young rats (each point represents data from a single rat), such that some rats fell within the range of young whereas others fell outside this range, demonstrating impairment. Dividing the aged rats according to a criterion of greater or less than 1 standard deviation from the mean of the young group yielded two equally-sized subgroups of aged rats: an “aged shifting-unimpaired” subgroup that performed identically to young, and an “aged shifting-impaired” subgroup that performed significantly worse (greater number of trials to criterion) than both the young and aged shift-unimpaired subgroups. B) and C) show data from the subsets of rats subsequently tested in the delayed response and water maze tasks, respectively. *p < 0.05.

Figure 4. Performance on the delayed response working memory task in young and aged rats, and relationships with set-shifting performance

A) All rats showed delay-dependent decrements in performance on the delayed response task, but aged rats were impaired relative to young. B) Aged shifting-impaired rats performed comparably to young on the delayed response task, whereas aged shifting-unimpaired rats performed worse than both shifting-impaired and young cohorts. C) Among aged rats, performance on the set-shifting task was significantly correlated with performance on the delayed response task at the 24 s delay, such that worse set-shifting predicted better working memory.

Figure 5. Relationships between performance in the set-shifting and water maze tasks

A) Aged rats performed significantly worse than young (greater cumulative search error) across the 4 blocks of training trials in the water maze. B) Both the aged shifting-unimpaired and shifting-impaired subgroups were impaired relative to young rats (greater cumulative search error), but the two aged subgroups did not differ from each other. C) Among aged rats, there was no correlation between performance on set-shifting and performance on the interpolated probe trials in the water maze (as assesed by the learning index measure – see text for details).