Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility

Abstract

Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training resulted in an immediate (at 4 mo of age) improvement in the animals' aggregate performance across a battery of five learning tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo (totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks, and variations of those tasks that required the animals to modify the previously learned response. Both attentional and learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.

Full text

10.1101/lm.2034711Access the most recent version at doi:
2011 18: 345-356Learn. Mem.
Louis D. Matzel, Kenneth R. Light, Christopher Wass, et al.
cognitive declines and cognitive inflexibility
Longitudinal attentional engagement rescues mice from age-related
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Research
Longitudinal attentional engagement rescues mice from
age-related cognitive declines and cognitive inflexibility
Louis D. Matzel,
1
Kenneth R. Light, Christopher Wass, Danielle Colas-Zelin,
Alexander Denman-Brice, Adam C. Waddel, and Stefan Kolata
Department of Psychology, Program in Behavioral Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA
Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1
mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective
attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm maze task that required
the mice to remember and operate on two sets of overlapping guidance (spatial) cues. As previously reported, this training
resulted in an immediate (at 4 mo of age) improvement in the animals’ aggregate performance across a battery of five learn-
ing tasks. Subsequently, these animals received an additional 3 d of working memory training at 3-wk intervals for 15 mo
(totaling 66 training sessions), and at 18 mo of age were assessed on a selective attention task, a second set of learning tasks,
and variations of those tasks that required the animals to modify the previously learned response. Both attentional and
learning abilities (on passive avoidance, active avoidance, and reinforced alternation tasks) were impaired in aged
animals that had not received working memory training. Likewise, these aged animals exhibited consistent deficits when
required to modify a previously instantiated learned response (in reinforced alternation, active avoidance, and spatial
water maze). In contrast, these attentional, learning, and perseverative deficits were attenuated in aged animals that had
undergone lifelong working memory exercise. These results suggest that general impairments of learning, attention, and
cognitive flexibility may be mitigated by a cognitive exercise regimen that requires chronic attentional engagement.
Cognitive deficits are a defining feature of the phenotype of
elderly humans (Riley and Riley Jr. 2000) as well as laboratory ani-
mals (Barnes and McNaughton 1985; Gallagher and Rapp 1997;
Markowska and Savonenko 2002a; Gould and Feiro 2005; Matzel
et al. 2008, 2009), and it has been estimated that as much as 25%–
50% of the age-related decline in cognitive/learning test perform-
ance is attributable to a perturbation of a latent influence on gen-
eral cognitive abilities (Sternberg 1997; Sternberg and Kaufman
1998; Plomin 1999). Relatedly, the proportion of variance between
individuals that is accounted for by general abilities increases ac-
ross the life span, accounting for as much as 80% of the variance
between elderly individuals as compared to only ≈40% among
the rest of the population (Plomin and Spinath 2002).
It has been proposed that a decline in the processing capacity
of working memory underlies much of the broad decline in cogni-
tive function that accrues with age (Salthouse et al. 2003). This
hypothesis is based on the widely held belief that components
of the working memory system are recruited to accomplish (to
varying degrees) any cognitive task, and thus are a critical deter-
minant of general (cf. fluid) intelligence (Conway and Engle
1996). In young adults, it has been suggested that variations in
working memory capacity and its related process, selective atten-
tion, may regulate general cognitive performance (Engle et al.
1999; Conway et al. 2003; Unsworth and Engle 2006), and similar
processes have been proposed to regulate general learning abilities
in genetically heterogeneous mice (Kolata et al. 2005, 2007; Light
et al. 2010; for review, see Matzel and Kolata 2010). In fact, in
mice, aging preferentially limits animals’ working memory
capacities (Matzel et al. 2008). This is potentially critical, as a dys-
regulation of “executive functions,” which are heavily dependent
on the implementation ofworking memoryand selective attention,
is often asserted to broadly impact cognitive functions in aged
human populations (Salthouse et al. 2003).
Related to the above-mentioned issues, it has recently been
reported that working memory/selective attention training can
have beneficial effects on performance across multiple cognitive
domains in both humans (Jaeggi et al. 2008) and mice (Light
et al. 2010). In a previous study, Light et al. (2010) provided young
adult CD-1 mice with extensive working memory training. Prior
to the working memory exercise (which in the human literature
is often described as “attentional engagement” [Stine-Morrow
2007]), the animals were trained to navigate for food in two dis-
tinct eight-arm radial mazes. During two subsequent weeks of
working memory training, the animals were required to perform
in both mazes simultaneously, that is, choices in one maze alter-
nated with choices in the other. As these two mazes shared a
common set of spatial cues, accurate performance in each maze
required that the animals maintain and segregate two sets of
overlapping information, simultaneously using that informa-
tion to independently navigate each maze. This training was
believed to tax the processing components of working memory
(i.e., capacity and selective attention) (Baddeley and Logie 1999;
Baddeley 2003), and in fact, was found to promote an increase
in selective attention in trained animals relative to both untrained
animals and animals trained on a version of the task with a min-
imal selective attention demand. More importantly, trained ani-
mals exhibited an improvement in performance across a battery
of five diverse learning tasks (that included fear conditioning,
spatial water maze, odor discrimination, passive avoidance, and
egocentric maze learning), suggesting that working memory exer-
cise directly impacted general cognitive performance in young
adult mice.
The above-mentioned results immediately raise two ques-
tions. First, would transient working memory training have
1
Corresponding author.
E-mail matzel@rci.rutgers.edu; fax (732) 445-2263.
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345 Learning & Memory
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lasting effects on general cognitive performance (Conway 2010)?
Although Light et al. (2010) demonstrated that working memory
training promoted an increase in general cognitive performance
at least 2 mo after the completion of training, 2 mo represents
only a fraction of the mouse’s life span. A second obvious question
raised by these results is whether chronic working memory train-
ing might slow (or mitigate) the onset of age-related cognitive
declines. In the present paper we address this second question.
Although it has previously been reported that “practice” on a spe-
cific task can maintain performance on that task across an ani-
mal’s lifespan (Markowska and Savonenko 2002a; Vicens et al.
2003), it is unclear whether more general cognitive training (as
would be instilled by a complex working memory/selective atten-
tion task) might have more broad protective effects across multi-
ple learning and/or cognitive domains.
To address the above issue, at 3 mo of age, mice were
trained on an intensive working memory task for 2 wk, and
were subsequently assessed for performance on a test of selective
attention and five learning tasks. As noted previously, working
memory training promoted an improvement in attentional and
learning skills. Results obtained from these young animals were
initially reported by Light et al. (2010). Upon completion of test-
ing, a cohort of these animals began a 14-mo regimen of working
memory training (or training on a control procedure with mini-
mal working memory demands) during which 3 d of additional
training was administered every 3 wk. At 18 mo of age (roughly
corresponding to 70 human years), animals underwent a series of
tests to assess learning and selective attention. In addition to def-
icits in acquisition and retention, elderly humans exhibit diffi-
culty in adapting previously learned responses to new situations
(Span et al. 2004; Pesce et al. 2005). This reflects on the distinction
between automatic (wherein fixed response patterns are effective
in unchanging conditions) and controlled (wherein a learned
concept is applied flexibly to changing conditions) forms of
information processing (Poldrack and Packard 2003). Thus in
the present paper, we also assessed the capacity of aged animals
for task switching (or reversal learning), an ability that is pre-
sumed to be more heavily reliant on “executive functions” than
is initial acquisition of a learned response (Salthouse 2005).
In all cases, the performance of aged animals (those having
undergone chronic working memory training and untrained con-
trol animals) was compared to the performance of a younger
(5 mo old) cohort.
Results
Task-specific learning and reversal performance
First we will summarize the performance of young control, old
control, and old animals that had undergone chronic working
memory training on the four learning tasks administered here
(i.e., step-down avoidance, reinforced alternation, shuttle avoid-
ance, and spatial water maze). These tasks are presumed to
impinge on different sensory, motor, motivational, and informa-
tion processing systems.
Step-down (passive) avoidance (ns ¼17 [OLD/WM], 9 [OLD/C],
12 [YOUNG/C])
Upon stepping from a safe platform, animals were exposed to
a presentation of a bright light and loud noise. The ratio of
post-training-to-pretraining step latencies is illustrated in Figure
1A. Groups differed in their performance on the passive avoidance
task, F
(2,35)
¼7.28, P,0.05. Planned comparisons indicated that
YOUNG animals performed better than old animals that had
not received working memory training (OLD/C), F
(1,35)
¼9.66,
P,0.01, but were statistically comparable to aged animals that
had been administered chronic working memory training
(OLD/WM), F
(1,35)
¼0.18, ns. Further, aged animals administered
working memory training performed better than old control
(OLD/C) animals, F
(1,35)
¼14.91, P,0.01. Finally, it should be
noted that in this task (based on only a single training trial),
aged animals that had not undergone working memory training
(Group OLD/C) exhibited no post-training increase in step-down
latency, suggesting that within these training parameters, old
mice were incapable of learning this simple task.
Reinforced alternation (ns ¼17 [OLD/WM], 8 [OLD/C], 12 [YOUNG/C])
Animals were trained to alternate between arms in a T-maze to
obtain reinforcement. To assess animals’ acquisition rates, a crite-
rion of four consecutive correct alternations was chosen, and the
trial at which this run of correct responses began was compared
across groups (see Fig. 1B1) revealing a significant difference,
F
(2,34)
¼14.11, P,0.001. Planned comparisons indicated that
YOUNG/C animals performed better than old animals that had
not received working memory training (OLD/C), F
(1,34)
¼18.96,
P,0.001, but were statistically comparable to aged animals that
had been administered chronic working memory training
(OLD/WM), F
(1,34)
¼0.50, ns. Further, aged animals administered
working memory training performed better than old control
(OLD/C) animals, F
(1,34)
¼29.46, P,0.001.
Animals received a total of 24 training trials, and thus by the
end of training had all received training that exceeded criterion by
an average of ≈16 training trials. At this point, conditions were
reversed such that animals were required to return to the arm
previously reinforced in order to obtain reinforcement (i.e., the
training conditions were switched from win-shift to win-stay)
(Fig. 1B2). During this phase of training, one animal was lost
from the OLD/WM group. Again, a comparison of trials-to-
criterion revealed a difference between groups, F
(2,33)
¼21.99.
P,0.001. Planned comparisons indicated that YOUNG/C
animals performed better than old animals that had not received
working memory training (OLD/C), F
(1,33)
¼43.59, P,0.001, but
were statistically comparable to aged animals that had been
administered chronic working memory training (OLD/WM),
F
(1,33)
¼3.23, P,0.10, although in this instance, young animals
did exhibit a tendency toward better performance. However, aged
animals administered working memory training performed better
than old control (OLD/C) animals, F
(1,33)
¼22.05, P,0.001.
Shuttle (active) avoidance (ns ¼13 [OLD/WM], 7 [OLD/C], 10 [YOUNG/C])
Animals were trained to associate the onset of a light and the
opening of a door with the subsequent (10 sec later) onset of
shock. The animals could avoid shock by moving through the
door to the opposite side of the box (and could always escape
shock after its onset). To assess animals’ acquisition rates, a crite-
rion of four consecutive successful avoidance responses was
chosen, and the trial at which this run of correct responses began
was compared across groups (see Fig. 1C1) revealing a significant
difference, F
(2,34)
¼14.11, P,0.001. Planned comparisons indi-
cated that YOUNG animals performed better than old animals
that had not received working memory training (OLD/C),
F
(1,34)
¼18.96, P,0.001, but were statistically comparable to
aged animals that had been administered chronic working mem-
ory training (OLD/WM), F
(1,34)
¼0.50, ns. Further, aged animals
administered working memory training performed better than
old control (OLD/C) animals, F
(1,34)
¼29.46, P,0.001.
Animals received a total of 24 training trials, and thus by the
end of training had all received training that exceeded criterion by
an average of ≈12 training trials. At this point, animals received
Attentional engagement and cognitive aging
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Figure 1. (A) Step-down (passive) avoidance. Old (18 mo) mice received working memory training (OLD/WM) or a control procedure (OLD/C) across
their lifespan. Young (6 mo) animals (Group YOUNG/C) received a treatment similar to Group OLD/C for 3 mo. All animals were then assessed for learn-
ing on a passive avoidance task. Illustrated are group means +standard errors. (B) Reinforced alternation and reversal. Old (18 mo) mice received working
memory training (OLD/WM) or a control procedure (OLD/C) across their lifespan. Young (6 mo) animals (Group YOUNG/C) received a treatment similar
to Group OLD/C for 3 mo. (B1) All animals were then assessed for learning on a reinforced alternation task. (B2) Subsequently, conditions were changed
such that reinforcement was consistently delivered in only one of the two opposing arms. Illustrated is the average number of trials to reach a pre-
established criterion of four consecutive correct responses (+standard error). (C) Shuttle avoidance and reversal. Old (18 mo) mice received working
memory training (OLD/WM) or a control procedure (OLD/C) across their lifespan. Young (6 mo) animals (Group YOUNG/C) received a treatment
similar to Group OLD/C for 3 mo. (C1) All animals were then assessed for learning to avoid shock in a one-way shuttle avoidance task. Illustrated is
the average number of trials to reach a pre-established criterion of four consecutive avoidance responses (+standard error). (C2) After all animals had
attained super-asymptotic levels of performance, conditions were changed such that shock could be avoided by remaining in the start compartment
(rather than shuttling to the opposite side of the box). Illustrated is the percent of trials (out of four after one reversal training trial) in which animals
made a successful avoidance response after conditions were reversed. (D) Spatial water maze reversal. Old (18 mo) mice received working memory train-
ing (OLD/WM) or a control procedure (OLD/C) across their lifespan. Young (6 mo) animals (Group YOUNG/C) received a treatment similar to Group
OLD/C for 3 mo. All animals were then trained to locate a hidden platform in a spatial water maze. Illustrated is the average (+standard error of the
mean) latency to locate the hidden platform during the final acquisition trials and then after the hidden platform was moved to a new location.
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five reversal trials wherein shock could be avoided by remaining
on the side of the box that contained the light CS. During this
phase of training, one animal was lost from the O/WM group.
On the first of these trials (and consistent with previous shuttle
training), all animals moved to the side opposite the light CS
(and thus all animals received shock). Of interest was the percent
of the remaining four trials in which the animals successfully
avoided shock. Again, comparison of the percent of trials with a
successful avoidance response indicated a difference between
the three groups, F
(2,33)
¼21.99, P,0.001 (Fig. 1C2). Planned
comparisons indicated that YOUNG/C animals performed better
than old animals that had not received working memory training
(OLD/C), F
(1,33)
¼43.59, P,0.001, but were statistically compa-
rable to aged animals that had been administered chronic working
memory training (OLD/WM), F
(1,33)
¼3.23, P,0.10, although in
this instance, young animals did exhibit a tendency toward better
performance. However, aged animals administered working
memory training performed better than old control (OLD/C) ani-
mals, F
(1,33)
¼22.05, P,0.001.
Spatial water maze (ns ¼16 [OLD/WM], 8 [OLD/C], 12 [YOUNG/C])
Animals were trained to locate a hidden platform submerged
below the surface in a tank of opaque water. Figure 1D (left panel)
illustrates the latency to locate the hidden platform recorded
across the last five of 25 training trials. Only the last five trials of
training are illustrated as no differences between groups were
observed in the acquisition phase of training, and in fact, all ani-
mals performed at high degrees of efficiency even on the initial
training trials. This likely reflects the fact that all animals had pre-
viously undergone water maze training, although during that
training, the maze was visually distinct from the present maze
(black water and surround instead of the present white), the
previous maze utilized a different set of visual cues, and the escape
platform was located in a different quadrant of the maze. Despite
the novelty of the present version of the task, apparently this prior
training conferred a substantial advantage to the animals when
learning this new version of the maze. In this regard, it is notable
that “pretraining” or adaptation to the conditions of a water maze
often protects animals from manipulations that are otherwise pre-
sumed to impact animals’ capacities for spatial learning (Cain
et al. 1996). Consequently, acquisition data in the present maze
provides no useful comparison between the groups, although it
is evident from Figure 1D that aged animals achieved a level of
performance that was comparable to young animals (indicative
of no functional deficit in the motor requirements of swimming
or the perception of visual cues). In contrast, when the hidden
platform was moved to a new location on the 26th trial, perform-
ance across groups was differentially affected. An ANOVA of the
data obtained on the last five training trials and the five reversal
trials indicated a significant effect of trials, F
(2,9)
¼2.13, P,
0.03. Planned comparisons found no differences between groups
on any of the five trials prior to reversal training (F≤1.02, ns),
indicating that the groups reached comparable levels of perform-
ance by the end of training. Likewise, the groups did not differ on
the first reversal trial (Trial 26), indicating comparable degrees of
disruption in performance (F≤0.86, ns) when the location of
the escape platform was shifted. However, old animals that had
not undergone working memory training (OLD/C) were slow to
recover from this disruption (i.e., on the second reversal trial;
Trial 27), differing from young animals, F
(1,18)
¼5.93, P,0.05,
and old animals that had undergone working memory training
(OLD/WM), F
(1,18)
¼9.08, P,0.01. Groups OLD/WM and
YOUNG/C did not differ on this (F¼0.11, ns). Comparable levels
of performance were observed on trials 28– 30 (the last three trials
of reversal training), F≤0.86, ns.
Selective attention
Upon completion of all learning tests, animals were assessed for
performance in a test of selective attention. Following overtrain-
ing on odor and visual discriminations (in separate, distinct
boxes), the animals performed a complex discrimination task to
assess attentional abilities. In these trials, the odor cues from the
odor discrimination box were introduced into the visual discrim-
ination box and acted as salient task-relevant distracters (in a
manner analogous to the human Stroop test). Animals received
four such trials, and the total number of errors was once again
recorded. Of interest was the number of errors made in the visual
discrimination with the odor cues acting as distracters relative to
the errors committed in the visual discrimination when the
odor cues were absent. Groups did not differ in errors committed
in the last four trials of visual discrimination prior to the introduc-
tion of the odor distracters (average number of errors per trial ¼
0.1, 0.08, and 0.05, Groups OLD/WM [n¼11], OLD/C[n¼6],
and YOUNG/C[n¼9], respectively), F
(2,23)
¼0.91, ns. However,
when odor distracters were added to the visual discrimination,
errors increased (Fig. 2), and did so differentially across groups,
F
(2,23)
¼3.48, P,0.05. Planned comparisons indicated that
Group OLD/WM performed better in this test of selective atten-
tion than did Group OLD/C, F
(1,23)
¼7.43, P,0.05. The nominal
deficit in Group OLD/C relative to Group YOUNG/C did not
reach statistical significance, F
(1,23)
¼1.84, ns.
General cognitive performance
Animals exhibited a wide range of variability in performance
across tasks, although some individuals consistently performed
better or worse than the median performance on all tasks, a result
that is consistent with prior work (Matzel et al. 2003, 2006; Kolata
et al. 2008) and indicative of a conserved influence on perform-
ance across tasks. To quantify these observations, first a principal
component analysis was conducted on the acquisition data, the
reversal data, and selective attention data from the subset of
mice that contributed data to all of these tasks (ns ¼11, 6, and
9, Groups OLD/WM, OLD/C, and YOUNG/C, respectively). To
that end, a correlation matrix (Table 1) was constructed and it
Figure 2. Selective attention. Animals performed odor discrimination
and visual discrimination in each of two distinct contexts. After attaining
superasymptotic (and near errorless) performance on each of these tasks,
the odor and visual cues were simultaneously presented in the context
that signaled the visual discrimination. This constituted a mouse analog
of the human Stroop test, where task-relevant distracters must be
ignored in order for the animal to perform efficiently. The errors across
four test trials (relative to errors in the simple discrimination) are plotted
as a function of group. Lifelong working memory training facilitated selec-
tive attention in aged animals.
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was observed that all correlations were in a positive direction,
indicative of a common source of variance across all cognitive
tests. (It is noted that for this analysis, with one exception, the
same data that contributed to the between-group analyses con-
tributed here. In the one exception, for the water maze, only the
second trial of reversal training [where relevant group differences
were expected and observed] contributed to the principal compo-
nent analysis.) Principal component analysis extracted a prin-
cipal factor that accounted for 37% of the variance across tasks
(Table 2). Performance indicative of all cognitive tests loaded in
a consistent direction on this factor, and all variables exhibited
moderate-to-strong loading weights. From this analysis, a single
factor score was derived for each animal. A factor score is analo-
gous to each animal’s average Z-score for the six tasks, with each
Z-score weighted by the extent to which the corresponding task
contributed to the principal factor. Factor scores served to rank
animals on the variable captured by the principal factor, where
positive values indicate overall performance that was better
than the group mean, and negative values indicate performance
that was worse than the group mean. Factor scores were separated
by group (OLD/WM, OLD/C, and Young/C) (see Fig. 3), and
ANOVA indicated a significant difference between groups,
F
(2,23)
¼50.68, P,0.0001. Planned comparisons indicated that
the aggregate performance of old animals that had not undergone
working memory training (OLD/C) was worse than that exhibited
by both old animals that had undergone working memory train-
ing (OLD/WM), F
(1,23)
¼95.9, P,0.0001, and from YOUNG/C
animals, F
(1,23)
¼77.64, P,0.0001. Old animals that had under-
gone working memory training did not differ from YOUNG ani-
mals, F
(1,23)
¼0.20, ns.
Noncognitive influences on cognitive performance
Owing to the rapid attrition (owing to death or intoleranceof food
deprivation) of aged subjects that began near the completion of
this experiment, an extensive set of sensory motor tests, like we
have previously administered to aged mice (Matzel et al. 2008),
were not administered here. However, several measures of mo-
tor function and exploration could be derived from the tests
described previously.
Swimming Speed (ns ¼11 [OLD/WM], 8 [OLD/C], 11
[YOUNG/C]). Animals’ performance in the water maze allowed
us to estimate swimming speed from the period of uninterrupted
swimming during the animals’ first exposure to the maze. Owing
to a video recording failure (which prohibited our reporting of
path lengths above), all of the animals that contributed latencies
were not available for the analysis of swimming speed. Of the ani-
mals that provided data, ANOVA revealed no overall difference
between groups, F
(2,27)
¼0.51, ns. However, young animals did
exhibit a tendency to faster swimming speeds (mean ¼6.22 cm/
sec +1.43 SEM) compared to old animals that had undergone
working memory training (4.18 cm/sec +1.32 SEM) or old
control animals (4.46 cm/sec +0.90 SEM). Planned comparisons
found no significant differences between groups.
Running speed (ns ¼15 [OLD/WM], 9 [OLD/C], 11 [YOUNG/C])
Animals were trained to run through a 32 cm alley to obtain a
food reward. After animals were performing at asymptotic levels
(during which they typically run without pausing) the time to
complete the run (from its initiation to completion) was recorded
and the average of three trials was used to compute running
speed. ANOVA revealed no difference between groups, F
(2,32)
¼
0.11, ns, and likewise, planned comparisons did not reveal any
differences between groups (means ¼36.45 +1.24, 36.69+2.13,
and 35.62 +1.95 cm/sec for Groups OLD/WM, OLD/C, and
YOUNG/C, respectively).
Exploration (ns ¼17 [OLD/WM], 9 [OLD/C], 11 [YOUNG/C])
No explicit measure of exploration was obtained throughout
this experiment. However, the latency to reach the goal box in a
Lashley maze prior to receiving any food in that maze (i.e., on
the first training trial) is a least in part indicative of an animal’s
propensity for exploration, as animals that reach the goal box
sooner (prior to receiving any food there) are judged to be more
prone to enter novel environments. ANOVA revealed no differen-
ces in the latencies between groups, F
(2,34)
¼1.22, ns. However,
Group OLD/WM did exhibit a tendency to shorter latencies
than either Groups OLD/C and YOUNG/C (means ¼53.7 +
7.75, 64.9 +17.3, and 77.36 +12.64 sec for Groups OLD/WM,
OLD/C, and YOUNG/C, respectively).
Body weights (ns ¼15 [OLD/WM], 9 [OLD/C], 11 [YOUNG/C]).
Body weights were monitored across the duration of this ex-
periment. Relevant to the present purpose, body weights were
compared across groups at the start of the cognitive testing
(18 mo [OLD] or 5 mo [YOUNG] of age). ANOVA indicated asig-
nificant difference between groups, F
(2,32)
¼4.69, P,0.02. Group
O/WM (mean ¼46.8 +0.80) and Group OLD/C (mean ¼46.6 +
Table 1. Matrix of correlations of performance in tests of acquisition, reversal, and selective attention
Selective
attention
Passive
avoidance
Reinforced
alternation
(acquistion)
Reinforced
avoidance
(reversal)
Shuttle avoidance
(acquisition)
Shuttle
avoidance
(reversal)
Water maze
(reversal)
SA 0.42 0.17 0.26 0.35 0.25 0.19
PA 0.42 0.58 0.29 0.02 0.35 0.13
RA (Acq) 0.17 0.58 0.38 0.04 0.55 0.32
RA_(Rev) 0.26 0.29 0.38 0.10 0.25 0.30
SHUT_(Acq) 0.35 0.02 0.04 0.10 0.02 0.11
SHUT_(Rev) 0.25 0.35 0.55 0.25 0.02 0.09
WM_(Rev) 0.19 0.13 0.32 0.30 0.11 0.09
Table 2. Unrotated principal component analysis of acquisition,
reversal, and selective attention performance
Factor 1 Factor 2
Selective attention 0.58 20.53
Passive avoidance 0.73 0.16
Reinforced alt. (acquisition) 0.61 0.34
Reinforced alt. (reversal) 0.79 20.03
Shuttle avoid. (acquisition) 0.23 20.81
Shuttle avoidance (reversal) 0.65 0.31
Water maze (reversal) 0.45 20.18
Eigenvalue 2.59 1.23
Proportion of variance 0.37 0.17
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2.30) did not differ, F
(1,32)
¼0.01, ns. However, GroupsO/WM and
OLD/C each differed from Group YOUNG/C (mean ¼42.07 +
0.94), F
(1,32)
≥6.05, Ps,0.02. These results indicate that
although aging was associated with weight gain, explicit working
memory training had no impact on this weight gain beyond that
which may have been promoted by the control training proce-
dure. Thus, the impact of working memory training on cognitive
performance is not likely attributable to a simple exercise effect.
The relationship of noncognitive variables to general
cognitive performance
To further characterize the relationship of variations in noncog-
nitive performance to general cognitive performance, a principal
component analysis was conducted on the acquisition, reversal,
and selective attention data, as well as noncognitive performance
data from the subset of mice that contributed to all of these tasks
(ns ¼11, 6, and 9, Groups OLD/WM, OLD/C, and YOUNG/C,
respectively). The results of this analysis are provided in Table 3.
Looking at Factor 1, again, all cognitive variables loaded consis-
tently in a moderate-to-heavy manner. Noncognitive variables
loaded moderately-to-weakly in an inconsistent manner. Of
note, swimming speed loaded most weakly (0.09), further suggest-
ing, like the other analyses described previously, that swimming
speed could not account for differences between individuals
(and hence groups) in the water maze reversal performance. Of
the noncognitive variables, running speed loaded most heavily
(20.45), but as none of the cognitive performance indices were
based on running speed, this moderate degree of loading is
unlikely to have impacted any of the cognitive performance meas-
ures (and instead may be a covariate of body weight). It should
also be noted that the direction in which running speed loaded
on this factor suggests (albeit weakly if at all) that slower running
speed was associated with better cognitive performance, further
indicating that running speed is unlikely to account for the
observed differences in cognitive performance between young
and old animals.
Noncognitive variables loaded more consistently and in a
moderate-to-heavy manner on Factor 2 of this principal compo-
nent analysis. In contrast, cognitive variables loaded inconsis-
tently on this factor. Although the amount of variability in
performance accounted for by this factor is quite low, the most
parsimonious explanation for the pattern of loadings across
Factors 1 and 2 is that the four noncognitive variables considered
here are not consistently related to the overall pattern of cognitive
performance expressed by these animals.
Discussion
Relative to young animals, aged animals that had not undergone
working memory training exhibited marked deficits in the acquis-
ition of learned responses that represent different learning
processes (i.e., “domains”), sensory, motor, and motivational re-
quirements, and presumably, neuroanatomical dependence.
Deficits were observed in reinforced alternation, passive avoid-
ance, and active avoidance. In two of these tasks (reinforced alter-
nation and active avoidance), as well as a third task (spatial water
maze), old animals that had not undergone working memory
training exhibited deficits when conditions were changed so as
to demand a new behavioral response to obtain the same desired
outcome, i.e., aged animals exhibited deficits in “cognitive flexi-
bility,” a capacity that is representative of what is characteristi-
cally described as an “executive function” (Salthouse 2005).
Consistent with the nature of these deficits, the aged animals
exhibited impaired performance on a specific test of selective
attention, a skill that is critical to the proper control of working
memory (Baddeley and Logie 1999; Conway et al. 2003; Matzel
and Kolata 2010). Thus, not only were aged animals impaired in
the acquisition of new learning, they exhibited broad deficits in
functions related to cognitive control and flexibility. In combi-
nation with previous work of our own (Matzel et al. 2008, 2009)
and others (e.g., Barnes 1979; Barnes and McNaughton 1985;
Markowska and Savonenko 2002b; Gould and Feiro 2005), these
results further indicated that aging impacts performance across
a wide range of basic learning domains, as well as higher cognitive
functions.
Studies of cognitive aging are often subject to interpretative
difficulties owing to the potential impact of noncognitive per-
formance variables on measures of cognition or learning. In a
prior analysis similar to the one reported here (Matzel et al.
2008), a wide range of sensory, motor, and emotional variables
Figure 3. General cognitive performance. Old (18 mo) mice received
working memory training (OLD/WM) or a control procedure (OLD/C)
across their lifespan. Young (6 mo) animals (Group YOUNG/C) received
a treatment similar to Group OLD/C for 3 mo. All animals were then
assessed for acquisition on three learning tasks (passive avoidance,
shuttle avoidance, and reinforced alternation), for reversal learning in
three tasks (shuttle avoidance, reinforced alternation, and spatial water
maze), and for selective attention. Performance measures on each of
these tasks were then subjected to a principal components analysis (see
Table 2). From this analysis, a factor score was derived for each animal
that represented its general learning performance. Average factor scores
for each group are plotted; brackets indicate standard errors. Lifelong
working memory training (OLD/WM) attenuated the general cognitive
decline that was observed in aged animals that had undergone a
control procedure that made minimal demands on working memory
(OLD/C).
Table 3. Unrotated principal component analysis of acquisition,
reversal, selective attention, and noncognitive performance
variables
Factor 1 Factor 2
Selective attention 0.61 0.55
Passive avoidance 0.72 20.15
Reinforced alt. (acquisition) 0.68 20.40
Reinforced alt. (reversal) 0.54 20.30
Shuttle avoid. (acquisition) 0.28 0.54
Shuttle avoidance (reversal) 0.74 20.07
Water maze (reversal) 0.34 20.27
Body weight 0.34 0.27
Running speed 20.45 0.34
Swimming speed 20.09 0.30
Exploration 0.37 0.82
Eigenvalue 2.88 1.95
Proportion of variance 0.26 0.18
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were assessed in combination with multiple measures of cognitive
ability. While aged animals were clearly distinguished from their
young counterparts on many noncognitive domains, factor anal-
yses indicated that those variations in noncognitive performance
(with the exception of body weight) accounted for little of the
variance in performance across the battery of cognitive tests.
Although only a small number of noncognitive variables were
assessed in the present study (i.e., swim speed, running speed,
exploratory tendencies, and body weight), a similar conclusion
can be drawn from these data. Although a tendency was observed
for slower swim speeds in old relative to young animals, these
performance measures had no consistent explanatory value in
describing cognitive performance although they did load consis-
tently on a separate noncognitive factor. It is also worth noting
that both groups of aged animals were heavier than their young
counterparts. Importantly however, old animals that had under-
gone working memory training did not differ in body weight
from old animals that underwent control training (i.e., training
with no explicit attentional or working memory demands). This
indicates that working memory training did not impact cognitive
performance through any effect on fitness (at least fitness related
to body weight). In total, these results indicate that old animals
are impaired in several measures of noncognitive performance,
but that these noncognitive variations are unlikely to explain
the differences in cognitive performance between young and
old animals or old animals that had undergone working memory
or control training procedures.
True longitudinal studies of cognitive aging with human
subjects are quite rare or are circumscribed in their duration.
Laboratory animals provide a practical means to overcome the dif-
ficulties associated with longitudinal studies of humans, but even
so, are uncommon relative to cross-sectional analyses. Attempts
to assess the effects of behavioral or environmental manipulations
on the development of age-related cognitive declines have been
relatively infrequent, although several examples should be noted.
For instance, it has been reported that repetitive lifelong exposure
from a young age promotes a preservation of object recognition
memory (as well as reduced anxiety and enhanced hippocampal
neurogenesis) in aged mice (Leal-Galicia et al. 2008). Most rele-
vant to the present study, it has been reported that in both rats
(Markowska and Savonenko 2002a) and mice (Vicens et al.
2003) early training in a spatial water maze protects animals
from the declines in performance in these mazes that typically
accompany aging. However, it is not clear from these studies if
early exposure to the water maze would promote performance
in other cognitive tasks or domains, and likewise, the underly-
ing process that is being impacted by water maze training. In
the present experiments, it was determined that a form of lifelong
cognitive exercise that specifically taxed working memory
capacity and/or selective attention preserved performance in
both a novel selective attention task (modeled after the human
Stroop test), as well as three distinct learning tasks (passive avoid-
ance, active avoidance, and reinforced alternation). Further, this
working memory/selective attention exercise allowed animals
to maintain a high level of cognitive flexibility, such that when
task demands were altered (or “reversed”) animals having under-
gone this exercise rapidly (and successfully) adapted to the new
conditions. (It is worth noting that prior to any test of reversal,
all animals were trained to a comparable high level of competency
on the initial learning task. This was a critical manipulation,
because reversal performance would be likely to vary as a function
of initial learning.)
Much speculation has arisen regarding the assertion that
aging differentially impacts what is commonly described as “exec-
utive function” (Salthouse and Ferrer-Caja 2003). Executive func-
tion is a theorized cognitive system that is said to control and
manage other cognitive processes. As such, working memory
and selective attention are believed to be central components of
the executive system. In prior research, we have demonstrated
that aspects of working memory (including both working mem-
ory capacity and span) are differentially impacted by aging (Mat-
zel et al. 2008). Further, Young et al. (2010) demonstrated that
although young and old mice exhibit similar learning rates on
an attentional-set-shifting task, aged mice were differentially
impaired in a test of extra dimensional shifting, a process that is
known to be mediated by the frontal cortex and is representative
of executive abilities. Like set shifting, reversal learning is thought
to depend heavily on selective attention (and thus executive
control). However, in the present data, reversal performance
did not appear to be differentially impacted (relative to simple
acquisition) by aging. In only one instance (in the spatial water
maze) were we sensitive to an effect of aging on reversal that
was not seen in initial acquisition. Nevertheless, inspection of
Table 2 does indicate higher loadings of reversal performance
than acquisition performance on the same task. Thus, the present
data does provide marginal evidence for a differential effect of
aging on behavioral tasks that are more heavily dependent on
executive-like functions.
In prior studies it has been observed that aged animals
exhibit considerably more variability in cognitive performance
than do their young counterparts (Lund et al. 2004; Matzel et al.
2008), so much so that aged animals could be segregated into
those with age-related impairments and those that had been
spared entirely. Only a trend toward such increased variability
was observed here. In a measure of aggregate performance across
the battery of cognitive tests (based on a comparison of factor
scores), the variability in aged control animals did not differ
from aged animals that had undergone working memory training
or their young counterparts (see Fig. 3). This homogeneity of var-
iance in aggregate performance (among genetically heterogeneous
mice) was observed despite the slight increase in variability of
aged animals in most of the individual cognitive tasks. Of partic-
ular note was the performance of aged control animals on the
explicit test of selective attention, where the variability in per-
formance of these animals was greater than twice that observed
in young animals or aged animals that had received working
memory training. As it has been our contention that selective
attention is likely to impact performance on the other cognitive
tests reported here (Yarkoni et al. 2005; Matzel et al. 2008;
Matzel and Kolata 2010), it is unclear why this increased variabil-
ity in selective attention did not translate into greater variability
in the measure of general cognitive performance. A better under-
standing of this seeming paradox might be obtained through
independent factor analyses of the performance of the individual
groups tested here. Unfortunately, the group sizes that existed at
the completion of this study were sufficiently small (owing to
attrition) to prohibit such individual analyses.
Based on a combined principal component analysis of the
performance on all of the cognitive tasks (including learning,
reversal, and selective attention tests) of young and old animals,
each animal in this study was assigned a factor score (analogous
to an average Z-score of an animal’s performance across all tasks),
and this score served to characterize the general learning abilities
of each animal relative to the others in this sample. A comparison
of the factor scores of young (YOUNG/C) and old (OLD/C) ani-
mals indicated significantly impaired general cognitive perform-
ance in aged animals. However, aged animals that had been
provided with lifelong working memory/selective attention
training (OLD/WM) exhibited general cognitive abilities that
were indistinguishable from their young counterparts. Thus, con-
sistent with recent theory (e.g., Stine-Morrow 2007), cognitive
aging is demonstrated here to be the expression of a combination
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of both an innate genetic predisposition, as well as life experience,
and contrasts with suggestions that cognitive decline is an immut-
able consequence of the aging process (Molden and Dweck 2006).
The data reported here suggest that the implementation,
through repeated exercise, of attentional engagement can miti-
gate the characteristic declines in cognitive abilities that typically
accompany aging (also see Kramer et al. 2004; Stine-Morrow et al.
2006). It is worth noting that subregions of the prefrontal cortex
(PFC) may play a critical role in the mediation of general cognitive
performance through their regulation of attentional control and/
or working memory capacity (Sawaguchi and Goldman-Rakic
1991; Durstewitz et al. 2000; Thurley et al. 2008; Kolata et al.
2010; for review, see Matzel and Kolata 2010). In fact, Kolata
et al. (2010) have reported that the expression levels of a cluster
of dopamine D1-related genes in the prefrontal cortex predict ani-
mals’ general cognitive performances. It is tempting to speculate
that working training might impact this same dopaminergic clus-
ter (or its functional constituents), and thus might modulate cog-
nitive abilities in a manner similar to that with which it modulates
innate cognitive abilities. Although the present work does not
allow us to evaluate this hypothesis, it has been reported that dop-
aminergic transmission is reduced in the PFC of aged rats, and
further, that direct stimulation of the PFC with dopamine D1
receptor agonists promotes an improvement in working memory
performance in those animals (Mizoguchi et al. 2009).
Materials and Methods
Subjects
Three groups of male CD-1 mice were used in this experiment.
Two groups of animals arrived in our laboratory at 45 d of age.
The third group arrived (also at 45 d of age) 13 mo after the ini-
tial two groups, such that at the initiation of critical behavioral
testing, two groups were 18 mo of age (“OLD”), and one group
was 5 mo of age (“YOUNG” n¼11). During their time in our
laboratory, these animals served only in this experiment, i.e.,
did not act as breeders or in any other capacity. Two groups of
old animals received either chronic working memory training
(“OLD/WM”, n¼18) or a control treatment (“OLD/C”, n¼9).
(The unequal group sizes reflect the fact that the animals used
here began as a cohort in a larger study [Light et al. 2010] that
was previously reported. Part of this cohort was used for purposes
not originally intended, leaving the group sizes as they presently
stand.) Throughout the course of working memory training, one
animal in each of the OLD conditions died, resulting in final ns
of 17 and 8. At the start of behavioral testing, young mice ranged
from 26.4 to 36.4 g, aged control mice from 31.1 to 42.9 g, and
aged working memory-trained mice from 32.9 to 42.8 g.
All animals were housed individually in clear shoebox cages
in a temperature and humidity controlled colony room and were
maintained on a 12-h light/dark cycle. In order to minimize
defensive behaviors (which can impede goal-directed behaviors)
that often occur in response to handling, from the time of arrival
in our laboratory until the start of the experiment, all animals
were handled by an experimenter (removed from their home
cages and held by an experimenter) for 60 sec/d, 5 d/wk.
Similar handling was administered in any weeks in which no
experimental manipulations were scheduled. Critical behavioral
testing required 10 wk to complete, such that testing of young
and aged mice was concluded at 7.0 and 20.5 mo of age,
respectively.
Food deprivation
For the cognitive tasks that required food deprivation, ad libitum
food was removed from the animals’ home cages at the end of
the light cycle 40 h prior to the start of training (and thus
encompassing the “rest” day between successive tasks). During
the deprivation period, animals were provided with food in their
home cages for 90 min/d during the last 2 h of the light cycle, and
thus were 16 h food-deprived at the time of training or testing.
This deprivation schedule was deemed “mild” (animals typically
lost ,5% of their free-feeding body weight during this period),
but was sufficient to maintain stable performance on these tasks.
Behavioral training and testing
Animals that would ultimately be tested at 18 mo of age were
assigned to one of two groups at 70 d of age. Animals were ran-
domly assigned to these groups, with the exception of balancing
for animal weights and exploratory tendencies based on a pretest
in an elevated plus maze. (Exploratory behavior is strongly pre-
dictive of general cognitive abilities [Matzel et al. 2003, 2006;
Grossman et al. 2007]; and thus served to balance the groups prior
to training.) Working memory training was given to one of these
two groups, whereas the other received training with similar sen-
sory and motor demands, but a modification that resulted in min-
imal reliance on working memory capacity or selective attention.
For working memory trained animals (OLD/WM), training was
based on a procedure used previously in our laboratory (Kolata
et al. 2005) and described in detail in Light et al. (2010). In brief,
mice were trained to asymptote on two distinct radial arm mazes,
where the animals could collect food at the end of each of the
eight arms. The mazes were located in the same room such that
they shared common extra-maze visual cues (which are used by
the animal to guide its search). After this initial training, the ani-
mals then performed concurrently on both mazes once a day for
12 d (constituting working memory training). During this train-
ing, mice alternated choices in the two mazes, and consequently,
were required to maintain a memory of the choices in each maze,
and segregate these memories despite the overlapping extra-maze
visual cues. Thus, this training taxed both the maintenance of
information as well as working memory capacity and selective
attention. A second group of OLD animals (OLD/C; “control”)
received radial arm maze training that equated for sensory and
motor experience but made minimal demands on working mem-
ory maintenance, capacity, or selective attention. For this train-
ing, animals were placed in each maze for an amount of time
that was identical to the time spent by animals undergoing work-
ing memory training. However, the animals were placed in the
mazes sequentially (as opposed to concurrently) and the food
rewards were located within 2 cm of the entrance to each arm
(as opposed to at the end of the arm) and were placed on the sur-
face of the alley (as opposed to in a recessed cup). Thus, in this
control training, animals could explore the maze and retrieve
food, but were not reliant on the visual cues or the demands on
working or selective attention that were imposed on animals
that were receiving working memory training.
After 12 d of working memory or control training, all animals
were assessed for acquisition of a learned response in five tasks
(Lashley Maze, spatial water maze, passive avoidance, fear condi-
tioning, and odor discrimination). Relative to animals that had
not received working memory training, animals that received
explicit working memory training exhibited an aggregate im-
provement in their performance across this battery of five tasks
as reported in Light et al. (2010). Upon completion of this initial
test, these animals continued to receive working memory or con-
trol training for approximately the next 15 mo. This chronic train-
ing was administered on three successive days at 3-wk intervals
throughout this period, such that at 18 mo of age, animals had
received an initial 12 d of this training followed by a total of 54
additional training sessions over the subsequent 14 mo.
When the above-described animals were 15 mo of age, an
additional group of 60 d old mice (n¼11) arrived in our labora-
tory. Upon arrival, these mice (young, control treatment;
“YOUNG/C”) were handled for 4 wk (as described previously).
Subsequently, to equate the experience of these animals to their
aged counterparts, they were administered the same learning
test battery that was previously administered to the OLD animals.
As this treatment was intended only to standardize the history of
the three groups, the data from this training is not relevant to
the present analysis and is not reported here. Upon completion
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of the learning battery (at 4 mo of age) until the time of critical
behavioral testing, mice in this group received equivalent food
deprivation and food rewards (delivered in their home cages),
as well as handling comparable to that administered to the
OLD/C group.
Tests of learning, reversal, and selective attention began
when the aged animals (group OLD/WM and OLD/C) were 18
mo of age and young animals (YOUNG/C) were 5 mo of age.
Two criteria were established for the inclusion and design of these
behavioral tests. As all animals in this experiment had previously
been tested in our standard battery of five learning tasks (Light
et al. 2010), behavioral tasks were designed to be as distinct as pos-
sible from those included in the original test battery. Second, we
anticipated that aged animals might be particularly sensitive to
tasks that demanded controlled processing or task switching
(i.e., cognitive “flexibility”) and, thus, tasks were included where
such manipulations were easily implemented. Cognitive perfor-
mance was assessed on the following four learning tasks, as well
as a task designed to isolate selective attention.
1. Win-shift (reinforced alternation)/win-stay. This procedure
was conducted in a T-maze with black Plexiglas walls and a grid
floor (1-cm squares) constructed of white Plexiglas. A 22 cm ×
10 cm (l ×w) start compartment led to a 10 cm ×10 cm central
(choice) compartment from which branched off two 42 cm ×
10 cm arms (perpendicular to the start compartment). One of
these arms was lined with 1.25-cm-wide vertical white stripes
spaced 1.25 cm apart. The arm was lined with 1.25-cm-wide hor-
izontal white stripes spaced 1.25 cm apart. All walls were 24 cm
high. The exit of the start compartment was segregated from the
central compartment by a remotely operated clear Plexiglas guil-
lotine door. The central compartment could be segregated from
the two arms by independent remotely operated clear Plexiglas
guillotine doors. At the end of each arm was a 3 cm ×2cm(w×
h) white plastic food cup.
Training was conducted over three consecutive days. On day
1, animals were acclimated to the maze and allowed to make four
forced choices. On the first exposure, the animal was held in the
start box for 30 sec, after which it was allowed to traverse the
maze; the door into the left arm was locked closed, and the right
door was open. A food reinforcer (32 mg chocolate flavored puffed
rice) was located in the food cup in the right arm. After consuming
the food, the animal was returned to the start box for a 20-sec
intertrial interval (ITI). On the second exposure, this procedure
was repeated, but the right door was locked and the left door
open. After a 20-sec ITI, this sequence was repeated for two addi-
tional exposures. Through this sequence of four forced choices,
the animals were acclimated to the maze.
On the subsequent day, trainingbegan. On all training trials,
each choice door was fully open. On Trial 1, a reinforcer was avail-
able in both food cups and the animal could make a free choice.
On the second trial, reinforcement was available in the arm not
entered on the first trial. If an animal chose the correct arm, the
location of the reinforcer alternated on the following trial. If an
incorrect choice was made, the animal was allowed to correct its
mistake and locate the food in the other arm. In either case, after
the reinforcer was consumed, the animal was placed back in the
start box to begin a 20-sec ITI. The animals’ choices were recorded
on each trial for the last 12 of the 13 trials. (As no error was possi-
ble on the first trial, data from this trial was not used.) The proce-
dure was repeated on the next day, providing a total of 24 training
trials.
On day 4, animals were subjected to a change in conditions
from win-shift to win-stay. All animals’ first choices were rein-
forced on day 4. Thereafter, trials proceeded in the manner of
days 2 and 3, except that the food reinforcer was consistently
delivered on the same side as the animals’ first choices. Thus,
the animal was required to suppress its learned tendency to alter-
nate choices.
2. Shuttle avoidance/passive avoidance. The shuttle box appara-
tus consisted of a rectangular box measuring 45.7 cm ×19.7 cm
(l×w). Aluminum walls measuring 18.7 cm high enclosed the
sides of the apparatus, whereas the base of the apparatus was com-
posed of a grid floor at which the bars were spaced 1.3 cm apart. A
transparent piece of Plexiglas served as the lid of the apparatus.
The apparatus was then further divided in half (lengthwise) by
an aluminum partition with a 7.6 ×7.6 cm doorway located
directly in the center at the level of the base. This doorway was
able to be blocked with a remotely operated clear Plexiglas door.
To enhance discrimination between the two sides of the appara-
tus, the wall of one side (side A) had black vertical stripes measur-
ing 1.9 cm in width and spaced 1.9 cm apart. A small light bulb
(CM 1819) was mounted at the top of the wall opposite the door-
way in side A. This light was normally off, and when operated,
served as a conditioned stimulus (CS). The grid floors of the
two sides (A and B) of the apparatus were wired to two independ-
ent shock generators, which generated a scrambled 0.6 mA foot
shock.
The apparatus was located in a dark room lit indirectly by one
25 W incandescent light bulb (3 Lux at the grid floor). On the day
prior to training, all animals were acclimated to the apparatus.
Acclimation to the apparatus consisted of placing each animal
in the apparatus for a period of 20 min with the center door
opened in order to allow access to both sides of the apparatus.
On the subsequent day, training began. On the first training
trial, the subject was placed in Side A for 60 sec with door blocking
access to side B. At the end of this 60 sec, the CS on side A was illu-
minated. Ten seconds after the onset of the CS, the floor of side A
was electrified and the door was opened. This ensured that the
subject would receive a shock before having the opportunity to
escape to side B. The subject was then allowed free access to Side
B, where upon entering, the shock was terminated (i.e., the ani-
mal could escape shock via an active shuttle response). All animals
successfully escaped shock on this first trial. Ten seconds after the
onset of the shock, both the CS and the shock were terminated,
and the center door was lowered. The subject was then left in
side B for 60 sec, after which it was moved back to side A to begin
a 60-sec interval prior to the onset of the CS (i.e., Trial 2). On all
trials subsequent to the first, the door was raised at the onset of
the CS, allowing the animal to avoid shock by moving to Side B
during the initial 10 sec of the light CS, or to escape the shock
by moving to side B after shock onset. The subjects received 5 d
of training with five trials per day. Of interest was the number of
training trials prior to stable initiation of successful avoidance
responding during the initial 10 sec of light presentation.
On the sixth day of training, each subject received two addi-
tional training trials (during which time all animals were exhibit-
ing stable avoidance responding). Conditions were then reversed
so as to require passivity to avoid shock. During five such reversal
trials, the subject was left in side A for 1 min, followed by the onset
of the CS and the opening of the center door. During these trials,
the floor of side B was electrified 10 sec after the onset of the light
and Side A remained safe. On these trials, a successful avoidance
response required that the animals inhibit their previously
learned shuttle response and instead avoid the shock passively
by remaining on side A. After the termination of shock, the ani-
mals were left on side A for 2 min before the CS and shock were
presented again.
3. Spatial water maze/reversed spatial water maze. This task
requires the animals to locate a submerged platform in a pool of
opaque water (from which they are motivated to escape). Absent
distinct intramaze cues, animals’ performances in this maze are
highly dependent on their integration of spatial cues (Morris
1981). The latency and the path length to locate the platform
decrease over successive trials, despite entering the pool from dif-
ferent locations on each trial. To differentiate this water maze
from the water maze that all animals had previously undergone
training in, the water color and surround was white (previously
black), visual cues were constructed from black placards (previ-
ously patterns of lights), and the start locations and platform loca-
tion was changed.
A round pool (140 cm diameter, 56 cm deep) was filled to
within 20 cm of the top with water that was clouded with a non-
toxic, water soluble white paint. A hidden 14 cm diameter white
platform was located in a fixed position 1 cm below the surface
of the water. The pool was enclosed by a ceiling high white curtain
on which five different black patterns (which served as spatial
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cues) were fixed at various positions. Illumination of the maze was
42 fear conditioning (FC) at the water’s surface.
On the day prior to training, each animal was confined to the
platform for 360 sec by surrounding the platform with a clear
Plexiglas cylinder. On the next two training days, the animals
were started from one of three positions for each trial such that
no two subsequent trials started from the same position. The ani-
mal was said to have successfully located the platform when it
remained on the platform for 10 sec. After locating the platform
or swimming for 90 sec, the animals were left or placed on the
platform for 10 sec, after which they were removed for 10 min
and placed in a holding box before the start of the next trial.
Each animal completed 25 total trials (6/d for four consecutive
days, and one additional trial on a fifth day). The latency and
path to find the platform was recorded for each trial. On the fifth
day (after the 25th training trial, the platform was moved to a new
position in the quadrant opposite that which contained the plat-
form on the previous 25 trials. Of interest was the animals’ per-
formances on the subsequent five trials (i.e., task reversal).
These trials in which the platform was located in a new position
proceeded in the same manner as the previous trials.
4. Step-down avoidance. In this assay, animals learn to suppress
their exploratory tendency in order to avoid aversive stimuli. The
animals are placed on a platform, and when they step down, are
exposed to an aversive stimulus compound comprised of a bright
light and loud oscillating tone (i.e., “siren”). To distinguish this
task from the previous step-down avoidance task, a different
chamber was constructed and a strong odorant was added to the
environmental enclosure.
A chamber with a white grid floor 16 ×12 cm (l ×w) illumi-
nated by a dim red light (4 FC) was used for both acclimation and
testing. An enclosed “safe” platform (10.0 ×5.0 ×5.0 cm, l×w×
h) was constructed of black Plexiglas and was located 4 cm above
the grid floor of a larger round arena (24 cm diameter). This safe
platform had one opening facing the grid floor, which allowed
the animal to step down onto the floor. The exit from the platform
was blocked remotely by a clear Plexiglas guillotine-style door.
When the door was opened, the animal could step off of the
safe platform, and upon making contact with the grid floor, would
initiate the aversive stimuli. An odor (28 g Vick’s VapoRub) was
added to the chamber to further distinguish it from the chamber
that had previously been used in the alternate version of passive
avoidance.
Animals were placed on the platform with the door closed,
confining them on the safe platform. After 5 min, the door was
opened and the latency of the animal to leave the platform and
make contact with the floor was recorded. Upon making contact,
the aversive compound stimulus was initiated for 4 sec, after
which the exit door of the safe platform was once again closed.
The animals were again confined on the platform for 5 min after
which the door opened and their latency to step onto the grid
floor was recorded for a second time. The ratio of the post-training
step latency to pretraining step latency served as each animal’s
index of performance.
5. Selective attention. To assess differences in selective atten-
tion it was first necessary to train the animals to perform odor dis-
crimination and visual discrimination in two related yet distinct
contexts (Context ODOR and Context VISUAL, respectively).
Odor discrimination: Rodents are adept at using odor to guide
their behavior. In this task, mice navigate through a square field
using unique odors. The animals learn to choose the food cup
that contains the target odor when given four choices. The food
cup locations vary randomly, but the accessible food is always
marked by the same target odor (in this case mint).
The odor discrimination chamber consisted of a black
Plexiglas 60-cm-square field with 30-cm-high walls, which was
located in a dimly lit room (10 Lux) with a high rate of air turn-
over. Each corner of the chamber was fitted with a 10-cm-wide
wall (aligned 45˚to each side wall), which was also constructed
of black Plexiglas and fit over the corners of the apparatus creating
a 10-cm-wide flat surface in each corner. Affixed to the base of
these interchangeable walls were food cups, which were affixed
flush with the base of the wall. The flat surfaces of these corner
panels could be backlit by a white LED, and each panel had a dis-
tinct pattern of holes forming one of four shapes: a circle, an X, a
triangle, and two parallel horizontal lines. For odor discrimina-
tion training, these patterns were never illuminated.
The food cup affixed to the base of these interchangeable
inserts was a square block of black Plexiglas measuring 7.5 ×
7.5 ×1.5 cm. In the center of the block was a food port measuring
1.5 cm in diameter and 1 cm in depth. This served as the rein-
forcer (30 mg portion of chocolate flavored puffed rice) location.
This food port was covered during training and testing with a slid-
ing piece of opaque Plexiglas measuring 42 ×17 ×1.5 mm. This
cover could pivot (in either direction) to expose the food port.
All cups also contained inaccessible food in a chamber covered
with screen cloth directly beneath the food port. This served as a
nontarget odor cue to ensure that the scent of the reinforcer would
not guide the animals’ behavior toward the target cup. A cotton
tipped laboratory swab that was loaded before each training trial
with 25 mL of lemon, mint, cinnamon, or almond flavored extract
(McCormick PURE Flavor Extracts) extended vertically from the
back corner of each cup. Mint was always the target odor and
was associated with the accessible food reinforcer. (It is noted
that animals were previously trained in a similar odor discrimina-
tion task in which mint served as the discriminative cue. However,
we did not intend in the present task to assess the acquisition of
this discrimination, but rather, to establish an odor cue that would
later serve in our assessment of selective attention.)
Each animal received 1 d of acclimation and 2 d of training.
On the acclimation day, the animals receivedfour trials in order to
train them to push the pivoting door in order to allow access to
the food ports. During these acclimation trials the cotton tip lab-
oratory swabs were placed in their relevant locations, but were not
loaded with odor extract and only a single food port was baited
with a reinforcer. On the first acclimation trial the animal was first
placed into a perforated transparent Plexiglas cylinder (11 cm in
diameter and 12.7 cm in height) located in the center of the train-
ing chamber for 20 sec, after which the cylinder was removed to
allow the animal to venture into the field. On this trial, the pivot-
ing doors on the food cups covered only half of the food port. On
the three successive trials (6 min ITI), the pivoting door was pro-
gressively closed so that by the fourth trial the food port was
completely covered.
On the subsequent two training days, each animal received
five training trials on each day. During this phase, the cotton tip
laboratory swabs were loaded with 25 mL of either mint, lemon,
almond, or cinnamon extract. On these trials, an accessible food
reinforcer was located under the pivoting door associated with
the mint odor. (On only the first trial, an additional reinforcer
was placed on the edge of the target cup.) At the beginning of
each training trial the animals were once again placed in the clear
Plexiglas cylinder located in the center of the apparatus for 20 sec.
The animal was then released, and remained in the field until the
food associated with the target odor was retrieved. At the end of
each trial, the animal was returned to a holding chamber for a
6 min ITI, during which time the food cups were rearranged
(i.e., located to different corners), but mint always remained as
the target odor. For each trial, the number of errors to retrieve
food was recorded. An error was constituted by the animal push-
ing a nontarget pivoting door enough to expose the food port,
and or returning to a previously opened nontarget cup.
Visual discrimination: In this task, the animals learned to
choose the target symbol among four possible choices to locate
food. The visual discrimination box was made distinct from the
odor discrimination box by the addition of white stripes on
the walls measuring 1.9 cm in width and spaced 1.9 cm apart.
The procedure proceeded exactly as specified for odor discrimina-
tion with the exception that the cotton laboratory swabs were not
loaded with extract and that the visual cues (back lights) were illu-
minated. Here the mice were trained to associate the two horizon-
tal lines with the location of the reinforcer. The total number of
initial training trials was also increased from 10 to 15 trials (over
3 d) as mice tend to learn about odor cues more quickly than vis-
ual cues (and animals had received no prior training on the visual
discrimination).
Attentional engagement and cognitive aging
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Following training on odor and visual discrimination, the
animals were given additional overtraining trials upon which
they received four odor discrimination trials and four visual dis-
crimination trials separated by 4 h (on each day). This training
phase continued until all animals reached an asymptotic level
of performance (defined as a total of two errors or less over the
final four training trials in any session). Following these overtrain-
ing trials the animals performed a complex discrimination task to
assess selective attention. In these trials, the odor cues from odor
discrimination training were introduced into the VISUAL discrim-
ination box, and thus acted as salient task-relevant distracters.
Animals received four such trials, and the total number of errors
was once again recorded. Previously, using a similar task, the abil-
ity to effectively attend to target cues and to ignore task-relevant
distracters has been reported to be a measure of selective attention
and was found to be related to the animals’ general cognitive per-
formances (Kolata et al. 2007).
Navigation in a Lashley III maze. This maze consists of a start
box, three interconnected alleys, and a goal box. Previous studies
have shown that over successive trials, the latency and number of
errors to find the goal decreases. When extra maze cues are mini-
mized, the animals tend to use egocentric methods (e.g., fixed
motor patterns) to locate the goal box. Here, it was our intention
to assess learning in the Lashley maze. However, performance in
this maze was clearly contaminated by prior training in a similar
maze (i.e., animals exhibited near asymptotic performance after
only a single training trial). Thus, acquisition data obtained on
this task was determined to be potentially misleading and thus
was not included in our analysis of cognitive performance.
However, upon achieving stable levels of performance, the ani-
mals’ running speeds could be estimated in this maze, and thus
was used as an index of motor fitness.
A Lashley III maze scaled for use with mice (see Matzel et al.
2003) was constructed from black Plexiglas and located in a dimly
lit room (10 Lux at the floor of the maze). A 3-cm-diameter white
circle was located in the center of the goal box, and 45 mg Bio-serv
food pellets (dustless rodent grain) was placed in the cup to moti-
vate the animals’ behaviors.
On two successive days, food-deprived animals received a
day of acclimation to the maze, followed by a single training
day. Prior to the day of acclimation, all animals received three pel-
lets of the reinforcer in their home cage. On the acclimation day,
each mouse was confined in each of the first two alleys of the maze
for 4 min, and in the final alley (containing the goal box) for
6 min. On this acclimation day, three pellets were placed in the
goal box. At the end of each period, the animal was physically
moved to the next alley. This acclimation exposure was intended
to adapt the animals to the apparatus prior to actual training. On
the subsequent training day, each animal was placed in the start
box and allowed to freely navigate the maze, during which time
their latency to locate the food was recorded. Upon locating and
consuming the food pellet, the animal was returned to its home
cage for a 25-min ITI, during which time the maze was cleaned.
The animals completed five trials during the single training day.
Running speed was determined based on each animal’s perform-
ance during Trials 4 and 5 (see Results for a description of this
analysis).
Analyses
To compare groups, one- or two-factor ANOVAs (where multiple
test trials could serve as a repeated measure) were used to compare
the groups’ performance. General learning abilities were assessed
with unrotated principal component analyses. For the principal
component analysis, the animal’s performance on learning tasks
was assessed during acquisition. For this purpose, data for each
animal on multitrial tasks were taken from the point in the acquis-
ition curve that was intermediate between initial performance
and terminal performance, i.e., in the middle of the acquisition
phase. For this purpose, the average performance of two trials
served as each animal’s performance on multitrial tasks (for addi-
tional detail, see Matzel et al. 2003). In the tasks in which there
was only one test trial (i.e., passive avoidance) we used training
parameters that we have previously found to result in subasymp-
totic responding during testing.
Across the course of testing, several animals in the aged
groups became noticeably weak and/or died, and in several
instances, apparatus malfunctions led to the elimination of one
or more animals from a particular test. The number of animals
that actually contributed to each task is provided in each section
of the results, and the reported degrees of freedom varied
accordingly.
To compare general cognitive performance across groups,
animals were assigned factor scores derived from the principal
component analysis. A factor score is analogous to an average
Z-score for each animal computed from the Z-scores obtained
for that animal on each task, with the Z-score for each task
weighted for the degree to which that task contributed to the prin-
cipal factor. The factor scores of young and aged animals were
compared to assess differences in general learning abilities across
the two ages.
Acknowledgments
This work was supported by grants from the National Institute of
Aging (PHS AG022698 and AG029289) and the Busch Foundation
to L.D.M.
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