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The Ultimate Intra-/Extra-Dimensional Attentional Set-Shifting Task for

Mice

Article in Biological Psychiatry · June 2013

DOI: 10.1016/j.biopsych.2013.05.021 · Source: PubMed

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ARCHIVAL REPORT
The Ultimate Intra-/Extra-dimensional Attentional
Set-Shifting Task for Mice
Diego Scheggia, Audrey Bebensee, Daniel R. Weinberger, and Francesco Papaleo
Background: Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of
several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set shifting in humans
are the Wisconsin Card Sorting Test and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift
task (ID/ED). These tasks have proven clinical relevance and have been successfully adapted for monkeys. However, similar tasks
currently available for rodents are limited, mainly because of their manual-based testing procedures. The current limitations of rodent
attentional set-shifting tasks are hampering translational advances in psychiatric medicine.
Methods: To closely mimic the Cambridge Neuropsychological Test Automated Battery ID/ED task in primates, we present the
development of a novel operant-based two-chamber ID/ED “Operon” task for mice.

Results: We show the ability of this novel task to measure attentional set shifting in mice and the effects of genetic and pharmacologic
manipulations of dopamine and glutamate. In genetically modified mice with reduced catechol-O-methyltransferase activity there was
selective improvement on extradimensional shift abilities and impairment of serial reversal learning. Chronic administration of
phencyclidine produced a selective impairment of extradimensional shift while producing a generalized decrease in latency to respond.
Conclusions: We demonstrate that this novel ID/ED Operon task may be an effective preclinical tool for drug testing and large genetic
screening relevant to the study of executive dysfunctions and cognitive symptoms of psychiatric disorders. These findings may help
elucidate the biological validity of similar findings in humans.

different perceptual dimensions (extradimensional shift [EDS])

Key Words: Attentional set shifting, catechol-O-methyltransferase,
executive functions, novel apparatus, phencyclidine, reversal
learning
ttentional set shifting is a measure of cognitive flexibility
within the same subject. This distinction is crucial because a
double dissociation or functional specialization between the
lateral (in monkeys and humans)/medial (in rodents) and orbital
regions of the prefrontal cortex (PFC) have been demonstrated.
That is, whereas the orbitofrontal cortex is selectively involved in

A and executive functions (1). It refers to the ability to switch

between arbitrary internal rules (“cognitive-attentional
sets”). The most widely used neuropsychological tasks for the
evaluation of this function in humans are the Wisconsin Card
Sorting Test (WCST) (2,3) and the CANTAB Intra-/Extra-Dimen-
sional set-shifting task (ID/ED) (4). These tasks have been used to
identify specific cognitive abnormalities in a wide range of mental
disorders including autism (5), schizophrenia (6), Parkinson’s
disease (7), obsessive-compulsive disorders (8), and attention-
deficit/hyperactivity disorders (9). The clinical relevance and solid
methodologic approach of the WCST and the ID/ED tests have
attracted interest in preclinical research (10,11). Importantly, these
tasks allow for the selective measurement of discriminative
learning, reversal learning, and switching of attention within the
same dimension (intradimensional shift [IDS]) and between
From the Department of Neuroscience and Brain Technologies (DS, FP),
Istituto Italiano di Tecnologia, Genova, Italy; Clinical Brain Disorders
Branch (AB, DRW), National Institute of Mental Health, National
Institutes of Health, Bethesda, Maryland; Lieber Institute for Brain
Development (DRW), Johns Hopkins University Medical Campus, and
Department of Psychiatry, Neurology, and Neuroscience and the
Institute of Genetic Medicine (DRW), Johns Hopkins School of
Medicine, Baltimore, Maryland; and Dipartimento di Scienze del
Farmaco (FP), Università degli Studi di Padova, Padova, Italy.
Address correspondence to Francesco Papaleo, Ph.D., Department of
Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia,
Via Morego 30, 16163 Genova, Italy; E-mail: francesco.papaleo@iit.it.
Received Jan 8, 2013; revised May 13, 2013; accepted May 17, 2013.
the reversal phases of these tasks, the lateral/medial PFC region
governs the EDS stages (1,12,13).
Despite their validity and utility in humans and nonhuman
primates (4), similar tasks currently available for rodents (14–18)
still suffer from limitations that dampen advancements in trans-
lating knowledge from animal research to psychiatric diseases.
For instance, in the current ID/ED tasks for rodents, the presence
of food reinforcers inside the choice stimuli might result in an
ambiguous interpretation of animal responses and potential bias
in choice making (10). Moreover, current set-shifting tasks are
manually intensive and time-consuming. These characteristics
limit the throughput of testing and application to and large-
scale genetic and/or drug-screening studies.
To overcome these limitations and enhance the potential trans-
lational applications of ID/ED shift paradigms in rodents, we present
here the development of a novel two-chamber, operant-based task
to test attentional set-shifting abilities in mice. This novel task closely
mimics the ID/ED task used in primates and circumvents the
problems of the earlier rodent versions. We also tested the
effectiveness of this new task in studies involving genetically
modified mice and pharmacologic manipulations. Specifically, we
tested catechol-O-methyltransferase (COMT) knockout mutant mice
because they are an established clinically relevant mouse model
with effects on executive cognition that recapitulate the pleiotropic
behavioral effects of COMT genetic modifications in humans (19,20).
COMT knockout mice have not been testable in a previously
available attentional set-shifting task (16), most likely because of
the interaction between the high-stress components of this manual
task and the anxiety-like behaviors of these mutant mice. Moreover,
we used our novel task to test the effects of chronic phencyclidine

0006-3223/$36.00 BIOL PSYCHIATRY 2013;]:]]]–]]]

http://dx.doi.org/10.1016/j.biopsych.2013.05.021 & 2013 Society of Biological Psychiatry.
Published by Elsevier Inc. All rights reserved.
2 BIOL PSYCHIATRY 2013;]:]]]–]]]
(PCP), a prominent pharmacologic model of schizophrenia that
produces cognitive executive dysfunctions related to PFC (21).
Furthermore, to assess whether our novel automated setup is really
a more effective translational ID/ED task compared with existing
standard systems, we contrasted the outcomes of our paradigm
with those obtained using a simplified operant-based task that has
been proposed for testing set-shifting abilities in rats (22).
Methods and Materials
Subjects
Testing was conducted in male mice, 3 to 7 months old,
C57BL/6J or COMT null mutant (COMT
/
), and their hetero-
zygous (COMT⫹/
) and wild-type (COMT⫹/⫹) littermates (16).
Distinct cohorts of naive mice were used for each experiment. See
Supplement 1 for detailed descriptions on animal housing,
apparatuses, statistics, food restriction, and testing procedures.
Novel Two-Chamber Operon ID/ED Task
See Figure 1 for details on the apparatus.
“Stuck-in-Set” ID/ED Paradigm. For habituation to the
apparatus, in the first two days, mice were habituated for 60
minutes to the apparatus with only neutral stimuli (Habituation 1)
and trained to move from one chamber to the other (Habituation 2).
Any nose poke into the nose-poke holes resulted in a pellet delivery
into the food receptacle. The next day, mice were trained to perform
two randomly presented simple discriminations (e.g., between
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D. Scheggia et al.
Velcro [3M, St. Paul, Minnesota] vs. film; light on vs. light off; peach
vs. sage) so that they were familiar with the stimulus dimensions
(Habituation 3). These exemplars were not used again. The mice had
to reach a criterion of 8 correct choices out of 10 consecutive trials
to complete this and each following testing stage. Performance was
measured in all phases of all experiments using number of trials to
reach the criterion; time (in minutes) to reach the criterion; time (in
seconds) from breaking the photobeams adjacent to the automated
door to a nose-poke response (latency to respond).
Figure 1. Schematic drawing of the novel two-chamber Operon appara-
tus. All procedures were approved by the Italian Ministry of Health and
local Animal Use Committee and in accordance with the Guide for the
Care and Use of Laboratory Animals of the National Institutes of Health
and the European Communities Council directives. The apparatus con-
sisted of two identical chambers with Plexiglas (Dobarca Srl., Genova, Italy)
walls and aluminum floor, separated by an automatic transparent door
that dropped to allow the mouse to change chambers. We used a two-
chamber setup to exclude any possibility of postural mediation of the to-
be-made response (27,46). Moreover, the two chambers also allowed us
for automatic and continuous stimuli changes without interfering with the
mouse. Each nose-poke hole was equipped with a series of changeable
stimuli that could vary in three perceptual dimensions (odor, sight, and
tactile; for stimulus exemplars used, see Table S1 in Supplement 1). We
built this apparatus to allow for manipulation of three perceptual
dimensions with a high number of stimuli for each dimension (at least
10 stimuli within each dimension). We devised stimuli with rodent-
appropriate dimensions and a sufficient number of exemplars of each
dimension to allow within-subject testing of all shifts, with novel stimuli at
every shift. This total-change design eliminates confounding factors that
can ambiguously affect the shift phases (47). Odors, lights, and textures
were switched on or placed in the required position just before the start
of a trial while the tested mouse was in the other chamber. (A) View from
the top of the entire apparatus and (B) view from the front of a single
chamber mimicking the mouse point-of-view during the test. 1, visual
stimuli (light-emitting diodes); 2, food magazine; 3, nose-poke hole; 4,
tactile stimulus (texture); 5, olfactory stimulus; 6, automatic sliding door; 7,
house light; 8, infrared photo beam for door control. The apparatus was
connected to a personal computer equipped with MED-PC IV software
(Med Associates, St. Albans, Vermont). Chambers (16  16  16 cm) were
separated by a transparent Plexiglas door (6). Infrared photobeams (8)
tracked the animal movements and controlled the opening/closing of the
automatic door to allow the mouse to change chambers. Each chamber
presented two nose-poke holes (3) with infrared photo beams, and,
between them, a food magazine (2) with photobeams delivering 14-mg
rodent tablets (5TUL; TestDiet, St. Louis, Missouri). A fan and a house light
(7) were located above each of the two food magazines. Each nose-poke
hole was equipped with a series of changeable stimuli that could vary in
three perceptual dimensions (odor, view, tact). For olfactory stimuli (5),
liquid odorants were diluted in mineral oil (1:20; M5904, Sigma Aldrich,
Dorset, United Kingdom) and presented on paper filter discs (15 uL, 2 cm)
enclosed in metal pods placed on a rotating wheel mounted beside each
nose-poke hole outside the chambers. Alternatively, we used two dilution
olfactometers (PHM-275; Med Associates) that controlled the presentation
of odor pairs inside the nose-poke holes (Figure S13 in Supplement 1). No
differences were found in mice tested with both methods (F1,14 ¼ .00; p ¼
.95). Ten odor stimulus exemplars were used for both methods (Table S1
in Supplement 1). For visual stimuli (1), light-emitting diodes were placed
on top of each nose-poke hole. Up to six color stimulus exemplars could
be presented to the test subject. Light stimuli were switched on in pairs
(red–green, yellow–blue, white–orange) and counterbalanced between
left and right nose-poke holes (Table S1 in Supplement 1). For tactile
stimuli (4), changeable floor textures, sliding under the floor, were
mounted in front of each nose-poke hole. There were up to 10 texture
stimulus exemplars (Table S1 in Supplement 1). Thus, the discriminative
association between a correct response (which will result in food delivery)
and a nose-poke hole could be varied by their odor, visual cue, or the floor
texture. Stimuli and operant-based rewarding components were located
in the same positions in chamber 1 and chamber 2. See also Figure S14 in
Supplement 1 for a photograph of the apparatus.
D. Scheggia et al. BIOL PSYCHIATRY 2013;]:]]]–]]] 3

Table 1. Example of the Intradimensional/Extradimensional Task with the other chamber where the stimuli cues were on. The series of
Stuck-in-Set and Two-Dimension Paradigms stages comprised a simple discrimination (SD), compound dis-
Dimension
crimination (CD), compound discrimination reversal (CDRe), IDS,
Discrimination Discrimination IDS reversal (IDSRe), a second IDS 2 (IDS2), IDS reversal 2 (IDS2Re),
Stage Relevant Irrelevant 1 2 EDS, and EDS reversal (EDSRe). The mice were exposed to the
tasks in this order so that they could develop a set, or bias,
SD Odor O1 O2 O1 O2 toward discriminating between the correct and incorrect nose-
CD Odor Light O1/L1 O2/L2 O1/L2 O2/L1 poke hole. See Table 1 for more details and an example of
CDRe Odor Light O2/L1 O1/L2 O2/L2 O1/L1 the task.
IDS Odor Light O3/L3 O4/L4 O3/L4 O4/L3 “Two-Dimension” ID/ED Paradigm. Habituation was identical
IDSRe Odor Light O4/L3 O3/L4 O4/L4 O3/L3 to the stuck-in-set ID/ED paradigm. To conduct the test, we used
IDS2 Odor Light O5/L5 O6/L6 O5/L6 O6/L5 a two-dimension ID/ED paradigm as in previous studies in
IDS2Re Odor Light O6/L5 O5/L6 O6/L6 O5/L5 humans, nonhuman primates, and rodents (4,13,15). The proce-
EDS Stuck-in-Set Texture Odor T1/O7 T2/O8 T1/O8 T2/O7
dure was identical to the stuck-in-set paradigm from the SD
EDSRe Texture Odor T2/O7 T1/O8 T2/O8 T1/O7
through the IDS2Re stages. In contrast, in the EDS, there were
EDS Two- Light Odor L7/O7 L8/O8 L7/O8 L8/O7 again new exemplars of both the relevant and irrelevant
Dimension dimensions (a total change design), but this time, the previously
EDSRe Light Odor L8/O7 L7/O8 L8/O8 L7/O7 relevant dimension was now the irrelevant dimension and vice
These paradigms were adapted from previous studies (7,14–16). Pairs versa (Table 1).
of stimuli (either Discrimination 1 or Discrimination 2) are randomly
presented in each stage, and the mouse must choose the correct stimulus Automated Visual-Cue/Left-Right Response Discrimination
in each pair. In this table, the correct exemplar is reported in bold. In the Set-Shifting Procedures
simple discrimination (SD) stage, the mice were introduced to a dimen- Mice were tested in standard operant boxes (Med Associates,
sion (odor, light, or texture) that was relevant throughout the tasks until
the extradimensional shift (EDS). In the SD stage of this example table, the
St. Albans, Vermont) equipped with two nose-poke holes with
stimuli presented in the two nose-poke holes differed along the odor recessed stimulus lights and, between them, a food magazine for
dimension (i.e., O1: vanilla vs. O2: lavender), and the mouse was rewarded food reinforcement delivery.
for choosing the correct exemplar (O1). For the compound discrimination Experiment 1. See Figure S10 in Supplement 1. Mice were
(CD), a second dimension was introduced, but the correct and incorrect habituated to the box and trained to poke into the nose-poke
exemplars remained constant. Once the subject reached the criterion on holes and retrieve the reward pellets from the magazine.
the SD stage, the CD begins in which the same exemplars of the relevant
dimension are presented overlaid at random by exemplars of a second,
Mice were also habituated to the stimulus lights to avoid
but irrelevant dimension, introduced as a confounding factor (e.g., L1: the confounding factors linked to the salience and novelty of
blue light vs. L2: yellow light). Two different discriminations are possible in the visual-cue lights during the successive testing phases (22).
this stage (either Discrimination 1 or Discrimination 2). For the reversals Visual-Cue SD: Mice were trained to poke into either the
(CDRe, intradimensional shift [IDS]Re, IDS2Re, and EDSRe), the exemplars illuminated nose poke-hole or the dark nose-poke hole to receive
and the relevant dimension were unchanged: the animal had to learn that a reward pellet. As with our novel task during the testing phases
the previously correct stimulus was now incorrect (e.g., lavender odor is
now rewarded). For the IDS, IDS2, and EDS, there were new exemplars of
of Experiments 1, 2, and 3, the program automatically shifted the
both the relevant and irrelevant dimensions (a total change design). In the exercise to the next discrimination after the mouse had reached
IDS (intradimensional shift), new exemplars (both odors and lights) are the criterion.
introduced, but the relevant dimension (odor in this example) remains the Set-Shift to Response Discrimination (EDS): Mice were required
same (e.g., strawberry is the correct choice). In the EDS of the stuck-in-set to disengage from the previously relevant visual-cue strategy and
paradigm, the mouse had to choose the correct hole after a new stimulus to use a response strategy by poking in the left or right nose-poke
dimension (e.g., the Texture, T1: coarse sandpaper vs. T2: fine sandpaper),
whereas the previously relevant dimension became irrelevant (in this case,
hole (randomly assigned) regardless of which hole was illumi-
odor). This procedure is only possible when three dimensions can be nated. We did not test mice on the response-to-cue shift because
manipulated. Indeed, at the EDS and EDSRe stages, the previously this procedure produced more variable data and was not as
irrelevant stimulus dimension was replaced by a new stimulus dimension sensitive to disruption following PFC inactivation (22).
which immediately became relevant. In this condition, failure to shift to Experiment 2. See Figure S11 in Supplement 1. Habituation
the new relevant dimension cannot be attributed to any previous learning and visual-cue SD were identical to Experiment 1.
about this dimension. Failure, therefore, reflected perseveration to the
previously relevant dimension. In the two-dimension EDS, the previously
Visual-cue SDRe: Mice were required to reverse their response.
irrelevant dimension (in this case, light) is now the relevant dimension. In Those that learned to respond at the illuminated nose-poke hole
the final stage (EDSRe), the reward contingencies are reversed. Each had to respond at the dark hole to receive a reward and
session was terminated after 40 minutes or if a mouse failed to make any vice versa.
response for 5 consecutive minutes, whichever came first. The test was Set-Shift to Response Discrimination (EDS): Identical to
then continued the next day. The order of the discriminations was always Experiment 1.
the same, but the dimensions and the pairs of exemplars (Table S1 in
Supplement 1) were randomly changed and equally represented within
EDSRe: Mice had to respond at the nose-poke hole opposite to
groups and counterbalanced between groups. that which was reinforced on the EDS.
Experiment 3. See Figure S12 in Supplement 1.
Visual-Cue SD and SDRe: Because the stimuli available were
To conduct the test, we used a stuck-in-set perseveration limited in this paradigm (i.e., light on–off and left–right response),
paradigm as in previous studies in humans and rodents (7,14,16). we removed the habituation phase to eliminate any possibility of an
This procedure is only possible when three dimensions can be a priori formation of a set or bias toward the stimuli presented. Mice
manipulated. A session started when a mouse was placed in one were directly trained in the visual-cue SD and SDRe as reported for
of the two chambers where all the stimuli were neutral. Then the Experiment 2. We also applied more stringent criterion (16 correct
transparent door was dropped to give the mouse access to the of 20 consecutive trials) and extra SD and SDRe.

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4 BIOL PSYCHIATRY 2013;]:]]]–]]] D. Scheggia et al.

Visual-Cue SD and SDRe: Mice went through a repetition of the

visual-cue SD and SDRe.
Set-Shift to Response Discrimination (EDS) and EDSRe: Identical
to Experiment 2.

Statistical Analysis
Results are expressed as mean ⫾ SEM throughout. One- or
two-way analyses of variance were used followed by Newman-
Keul’s test for post hoc analysis. The accepted value for signifi-
cance was p ⬍ .05.

Results
The Novel Two-Chamber ID/ED Operon Task Consistently
Measures “Stuck-in-Set” Attentional Set Shifting
To overcome the limitations of the current available attentional
set-shifting tasks for rodents and to closely mimic the WCST and ID/
ED tasks used in human and nonhuman primates, we generated a
novel two-chamber ID/ED apparatus for mice (Figure 1). We first
tested C57BL/6J adult mice using an ID/ED stuck-in-set paradigm
(14,16) (Table 1). This refined procedure is able to distinguish
different components of set shifting and is a more selective
measure of frontal lobe functioning in humans (7,23).
The analysis of mice performance revealed a discrimination effect
for the number of trials (F8,168 = 9.23; p ⬍ .0001) and time (F8,168 =
8.62; p ⬍ .0001) required to reach criteria. Indeed, mice needed more
trials (p ⬍ .05; Figure 2A) and more time (p ⬍ .05; Figure 2B) to solve
the EDS stage compared with CD, IDS, IDS2, and EDSRe stages. No
differences in performance were observed between mice tested
with different dimensions (See Results and Figures S1 and S2 in
Supplement 1). Thus, similar to previous studies in primates (13,24), the
mice needed more trials and more time to solve the EDS stage
compared with the previous and following stages, suggesting the
development of an attentional set. Also, the analysis of the latency to
respond showed a significant discrimination effect (F8,200 = 42.59; p ⬍
.0001). In particular, mice improved their speed to respond over
consecutive stages as demonstrated by a significant decreased in
latency to poke at the IDS2 compared with IDS, CD, and SD stages
(p ⬍ .0005; Figure 2C). Moreover, the latency to respond increased
during the EDS stage compared with the previous IDS2 and IDS2Re
and successive EDSRe stages (p ⬍ .05; Figure 2C). Because the latency
to respond has been considered an index of decisional processing (25),
these results further suggest that mice encountered some sort of Figure 2. The novel two-chamber intra-/extradimensional Operon task
problem processing the new discriminative rule during the EDS. Thus, reliably measures attentional set shifting abilities in mice. (A) Trials and (B)
time (in minutes) needed to reach the criterion in the different stages of
with this novel task, the higher number of trials and time needed to
the intra/extradimensional Operon task. (C) Time (in seconds) elapsed
solve the EDS was concomitant with higher latency to make a between the opening of the divider door and a nose-poke response
response (slower speed of processing). (latency to respond) during the different stages of the task. Twenty-six
Mice also required more trials (p ⬍ .005; Figure 2A) and time mice were tested; four mice were excluded because they were not reliably
(p ⬍ .05; Figure 2B) to solve the first reversal stage (CDRe) compared poking to retrieve the food reinforcement during the training or were not
with the initial CD. No effect of reversal learning was found in the able to finish the entire procedure. All other mice readily learned to poke
in the holes for food rewards and were able to perform the multiple
following stages (p ¼ .73). Moreover, reversal performance improved
sequences of discriminations (see Results and Figure S4 in Supplement 1).
from CDRe to IDSRe to IDS2Re (p ⬍ .0005; Figure 1A, 1B). These results (A) *p ⬍ .05 vs. compound discrimination (CD), intradimensional shift
are consistent with the previous manual version of the ID/ED task (16) (IDS), IDS2, IDS2 reversal (IDS2Re), and extradimensional shift reversal
and further strengthen evidence of the formation of an attentional set (EDSRe); (B) *p ⬍ .05 vs. CD, IDS2, IDS2Re, and EDSRe. (A, B) #p ⬍ .05,
(26). These results demonstrate that this novel paradigm is well suited
##
p ⬍ .005 vs. CD, IDSRe, and IDS2Re. (C) *p ⬍ .05 vs. IDS2, IDS2Re, and
for testing attentional set-shifting abilities in mice. EDSRe. Note that the mice were able to complete the entire task in 5–9
days in all experiments reported in Figures 2–5. Values represent mean ⫾
SEM throughout Figures 2–7. SD, simple discrimination.
Selective Improvement in Attentional Set-Shifting Abilities
but Serial Reversal Learning Impairment in COMT
Knockout Mice labor-intensive procedures of the currently available manual tasks
The study of genetically engineered mice in ID/ED tasks has (10,27). COMT genetic variations have been associated with
been limited by the variability of methodologic conditions and differential performances in the WCST, ID/ED, and equivalent

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D. Scheggia et al.
tasks (16,19,20). In particular, based on human and mouse studies
(16,28,29), individuals with decreased COMT activity should show
improved attentional set-shifting abilities. To investigate in our
novel task the effect of genetic variation that leads to reduced
COMT activity, we tested COMT
/
, ⫹/
, and their ⫹/⫹
littermates.
The performance of the COMT⫹/⫹ mice followed the same
pattern shown by the C57BL/6J mice tested in the previous
experiment (Figure 3; Results and Figure S3 in Supplement 1).
In contrast, ⫹/
and
/
mice did not show an increase of
trials, time, and latency to solve the EDS when compared with
the CD, IDS, IDS2, IDS2Re, and EDSRe stages. Indeed, ⫹/
mice
needed fewer trials and less time to complete the EDS
compared with IDS2Re (p ⬍ .05; Figure 3A, 3B). Moreover,
analysis of EDS performance revealed a genotype effect for trials
(F2,20 ¼ 7.35; p ⬍ .005), time to reach the criteria (F2,20 ¼ 4.98; p ⬍
.05) and for the latency to respond (F2,43 ¼ 12.17; p ⬍ .0005).
BIOL PSYCHIATRY 2013;]:]]]–]]] 5
Figure 3. Selective improvement in attentional set
shifting abilities but impaired serial reversal learning in
catechol-O-methyltransferase (COMT)⫹/
and COMT
/

mice. (A) Trials and (B) time (in minutes) needed to
reach the criteria and (C) latency to respond (in seconds)
during the different stages of the attentional set-shifting
task. Ten COMT⫹/⫹, 11 ⫹/
, and 7
/
mice were
tested; 1 COMT⫹/⫹, 2 ⫹/
, and 2
/
mice were
excluded because they were not reliably poking to
retrieve the food reinforcement during the training or
were not able to finish the entire procedure. All the
other mice readily learned to poke in the holes for food
rewards and were able to perform the multiple
sequences of discriminations (see Results and Figure S5
in Supplement 1). Note that the performance of the
COMT⫹/⫹ mice followed the same pattern as that
shown by the C57BL/6J mice tested in the previous
experiment. COMT⫹/⫹ mice required more trials (p ⬍
.05; Figure 3A) and more time (p ⬍ .05; Figure 3B) to
solve the extradimensional shift (EDS) and showed
increased latency during the EDS (p ⬍ .005; Figure 3C).
Moreover, COMT⫹/⫹ mice required more trials (p ⬍ .05;
Figure 3A) and time (p ⬍ .05; Figure 3B) to solve the first
reversal stage (i.e., compound discrimination reversal
[CDRe]), and their reversal performance improved from
CDRe to intradimensional shift reversal (IDSRe) to the
second IDS reversal (IDS2Re; p ⬍ .0005; Figure 3A–3B).
##
p ⬍ .005 and #p ⬍ .05 EDS performance vs. IDS/IDS2/
IDS2Re/EDS reversal (EDSRe); and CDRe performance
versus compound discrimination (CD). *p ⬍ .05, **p ⬍
.005, ***p ⬍ .0005 vs. performance of COMT⫹/⫹ at same
stage. SD, simple discrimination.
Compared with COMT⫹/⫹, in the EDS stage, COMT⫹/
and
COMT
/
mice required fewer trials and less time to reach criteria
(p ⬍ .05; Figure 3A,B) and were faster in making a nose-poke
response (p ⬍ .005; Figure 3C). Thus, as hypothesized by previous
human and mouse studies (16,28,29), genetic variation leading to
relative reduction of COMT activity produced an improvement of
EDS abilities. Moreover, this novel paradigm might be less stressful
for mice than the “digging” manual version because this same
strain of mutant mice failed to perform the manual task,
presumably because of their high anxiety-like behaviors (16).
Interestingly, although COMT⫹/
mice required more trials
and time to complete the CDRe than the initial discriminations,
similar to their control littermates (p ⬍ .05; Figure 3A,B), they did
not improve the reversal performance from CDRe to IDS2Re (p ¼
.28) as their ⫹/⫹ counterparts did. Moreover, COMT⫹/
showed
impaired reversal performance compared with ⫹/⫹ mice during
the IDS2Re because they needed more trials and time and longer
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6 BIOL PSYCHIATRY 2013;]:]]]–]]]
latency to respond (p ⬍ .05; Figure 3A,C). These results suggest
that partial COMT genetic reduction produces a selective impair-
ment of serial, but not initial, reversal learning.
Selective Impairment in Attentional Set-Shifting Abilities in
Chronic PCP-treated Mice
In rats, both acute (30) and chronic (31) PCP regimens
have been shown to selectively induce EDS cognitive deficits
using the “digging” manual version of the task. In contrast,
using this previous task, chronic PCP treatment failed to
show a similar impairment in mice (32). Thus, we tested in
our task C57BL/6J mice after chronic administration of saline
or PCP.
Significant discrimination  treatment interactions were
present for the trials (F8,104 ¼ 3.77; p ⬍ .005) and for the time
(F8,104 ¼ 4.01; p ⬍ .0005) needed to complete the task
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D. Scheggia et al.
Figure 4. Selective impairment in shifting of an atten-
tional set following chronic phencyclidine (PCP) treat-
ment. (A) Trials and (B) time (in seconds) needed to
reach the criteria and (C) latency to respond in the
different stages of the intra-/extradimensional Operon
task. Ten vehicle- and eight PCP-treated mice were
tested. One vehicle- and one PCP-treated mice were
excluded because they were not able to finish the entire
procedure. All the other mice readily learned to poke in
the holes for food rewards and were able to perform the
multiple sequences of discriminations (see Results and
Figure S6 in Supplement 1). The noncompetitive antago-
nist of the N-methyl-D-aspartate/glutamate receptor PCP
(phencyclidine HCl, 5 mg/kg, intraperitoneal; Sigma,
Dorset, United Kingdom) was dissolved in physiological
saline (.9% NaCl) and injected in a volume of 10 mL/kg.
Control mice were injected with the same volume of
saline. Animals were treated with PCP or saline once
daily for 14 consecutive days and after a 7-day washout
period the two-chamber intra-/extradimensional Operon
task started. The PCP dose used (5 mg/kg) was based on
a previous study demonstrating that this dose in mice
did not affect discrimination learning (48). Chronic
treatment was used, rather than acute, on the basis that
PCP long-term administration produces more selective
frontal cognitive deficits, which may better model frontal
lobe dysfunctions than those exhibited by animals
treated with a single dose (21). #p ⬍ .05, ###p ⬍ .0005
vs. all the other stages same treatment. *p ⬍ .05, ***p ⬍
.0005 vs. vehicle-treated mice at same stage. CD,
compound discrimination; EDS, extradimensional shift;
EDSRe, EDS reversal; IDS, intradimensional shift; IDS2,
second IDS; IDS2Re, IDS2 reversal; SD, simple
discrimination.
discriminations. Similar to untreated C57BL/6J, vehicle-treated
mice showed poorer performance in the EDS as demonstrated
by increased number of trials (p ⬍ .05; Figure 4A) to solve the EDS
compared with all the other stages and increased time (p ⬍ .05;
Figure 4B) compared with IDSRe, IDS2, IDS2Re, and EDSRe. More
important, consistent with findings in rats (30,33), compared with
vehicle-treated mice, PCP-treated mice required more trials (p ⬍
.0005; Figure 4A) and more time (p ⬍ .0005; Figure 4B) to solve
the EDS stage, whereas no PCP-dependent difference was present
in any other stage (p ⬎ .10). The analysis of the latency to
respond showed a discrimination  treatment interaction effect
(F8,240 ¼ 11.47; p ⬍ .0001). Similar to untreated C57BL/6J, vehicle-
treated mice showed an increase in the latency to respond in the
EDS compared with IDS2Re and EDSRe stages (p ⬍ .05; Figure 4C).
Moreover, compared with vehicle-treated mice, PCP treatment
decreased the latency to respond in the SD, CD, CDRe, IDS, and
D. Scheggia et al.
Figure 5. The novel two-chamber Operon task reliably measures atten-
tional set shifting in mice also with a two-dimension intra/extradimen-
sional paradigm. (A) Trials and (B) time (in minutes) needed to reach the
criterion in the different stages of the intra/extradimensional Operon task
using a two-dimension paradigm. (C) Time (in seconds) elapsed between
the opening of the divider door and a nose-poke response (latency to
respond) during the different stages of the task. Thirteen mice were
tested; three mice were excluded because they were not reliably poking
to retrieve the food reinforcement during the training or were not able to
finish the entire procedure. The other mice readily learned to poke in the
holes for food rewards and were able to perform the multiple sequences
of discriminations (see Results and Figure S7 in Supplement 1). (A, B) #p ⬍
.05 vs. compound discrimination (CD) and second intradimensional shift
reversal (IDS2Re), *p ⬍ .05 vs. CD, intradimensional shift (IDS), IDS2,
extradimensional shift reversal (EDSRe). (C) *p ⬍ .05 vs. IDS2, IDS2 reversal
(IDS2Re), and EDSRe. CDRe, compound discrimination reversal; SD, simple
discrimination.
EDS stages (p ⬍ .05; Figure 4C). These results demonstrate that,
despite the chronic injection manipulations, all the mice were
able to form an attentional set equivalent to our previous
experiments (Figure S3 in Supplement 1). Moreover, we observed
a selective impairment on EDS produced by chronic PCP
administration.
BIOL PSYCHIATRY 2013;]:]]]–]]] 7
The Novel Two-Chamber ID/ED Operon Task Consistently
Measures “Two-Dimension” Attentional Set Shifting
Another condition to measure attentional set-shifting ability
used both in primates and rodents (13,15,24), but that involves
the use of only two dimensions, requires a shift of the response
set to the previously irrelevant dimension. To investigate if our
novel two-chamber task might also reliably measure this two-
dimensional ID/ED performance, we tested another cohort of
C57BL/6J using this other paradigm (Table 1).
A discrimination effect was present for the number of trials
(F8,72 ¼ 3.66; p ⬍ .005) and time (F8,72 ¼ 4.65; p ⬍ .0005) needed
to reach criteria. Mice required more trials (p ⬍ .05) and more
time (p ⬍ .05) to solve the EDS compared with CD, IDS, IDS2, and
EDSRe (Figure 5A,B). The analysis of the latency to respond
showed also a significant effect of discrimination (F7,63 ¼ 9.98;
p ⬍ .0005). In line with our previous results (Figure 2C), the
latency to make a choice was increased during the EDS compared
with previous IDS2 and IDS2Re and successive EDSRe (p ⬍ .05;
Figure 5C). Interestingly, initial evidence shows that the same
pattern of ID/ED difference was still present when mice were
retested a second time or when the sequence of the stages was
changed (see Results and Figures S8 and S9 in Supplement 1).
Finally, the first reversal (CDRe) was again more difficult com-
pared with initial discrimination because mice needed more trials
(p ⬍ .05; Figure 5A) and more time (p ⬍ .05; Figure 5B) to
complete this stage. Moreover, performance on consecutive
reversal stages improved from CDRe to IDSRe to IDS2Re (p ⬍
.05). These results demonstrate that our novel Operon task is
suitable for measuring attentional set formation and shifting also
using a two-dimension ID/ED paradigm and highlight the
flexibility and reliability of this novel apparatus.
The Automated Visual-Cue/Left-Right Response
Discrimination Set-Shifting Procedure Does not Reliably
Measure Attentional Set-Shifting Abilities in Mice
To investigate the efficacy of a simplified automated paradigm
previously proposed for testing attentional set-shifting abilities in
rats (22,34) and to compare its outcomes with our novel ID/ED
Operon task, we tested C57BL/6J mice in this standard operant
procedure.
We first tested whether this automated procedure might
reliably measure attentional set-shifting abilities in mice (Experi-
ment 1; Figure 6 and Figure S10 in Supplement 1 for details). To
more closely model our novel task and the equivalent human
tasks and to strengthen the possible formation of an attentional
set, we then added to the paradigm two within-set reversal
stages (Experiment 2; Figure 6 and S11 in Supplement 1 for
details). As a final attempt to further increase the sensitivity of
this task, we made the criterion more stringent and introduced
a repetition of the SD and SDRe stages before the EDS (Experi-
ment 3; Figure 7 and S12 in Supplement 1 for details). Overall,
these results indicate that these operant procedures might be
useful to study reversal learning but that they are not able to
reliably measure attentional set-shifting abilities.
Discussion
In this study, we present the development of a novel two-
chamber ID/ED Operon task for rodents that overcomes the major
limitations of the previous manual versions and of the first
versions that attempted its automation. This paradigm is analo-
gous to the WCST and ID/ED tasks commonly used in human and
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8 BIOL PSYCHIATRY 2013;]:]]]–]]] D. Scheggia et al.

Figure 6. Automated visual-cue/left-right response discrimination set-shifting procedures did not reliably measure attentional set shifting abilities in mice.
Trials and time (in days) needed to reach the criteria during the simple discrimination (SD) and extradimensional set-shifting (EDS) stages in Experiment 1
(A, B), and during the SD, simple discrimination reversal (SDRe), EDS, and EDS shifting reversal (EDSRe) stages in Experiment 2 (D, E). Time (in seconds)
elapsed between the appearance of the stimulus light and a nose-poke response (latency to respond) during the different stages in Experiment 1 (C) and
2 (F). Note that the only difference between Experiment 1 and 2 was the addition of the reversal stages following the different discriminations. A total of
10 mice in experiment 1 and 17 mice in experiment 2 were used; 2 mice were excluded in Experiment 2 because they were not reliably poking to retrieve
the food reinforcement during the training. All of the other mice readily learned to poke into the nose poke holes and to discriminate the stimuli.
Experiment 1: the performance of mice showed a significant effect for the number of trials (F1,9 ¼ 38.50; p ⬍ .0005) and for the time needed to complete
each stage (F1,9 ¼ 39.24; p ⬍ .0005). In particular, mice needed fewer trials (p ⬍ .0005; Figure 6A) and less time (p ⬍ .0005; Figure 6B) to reach criteria in
the EDS compared with the SD stage. This is in contrast to the results from the novel Operon task (Figures 2–5) and with previous findings in humans and
monkeys (13,24) showing that the EDS stage should require more time and more errors to be solved. Indeed, these results suggest that mice did not
reliably form an attentional set to the visual-cue dimension. Despite this, we observed a tendency of effect in the latency to make a nose-poke response
(F1,9 = 4.96; p = .05). In particular, after presentation of the stimuli, mice tended to make a response slower in the EDS compared with the SD stage (p =
.05; Figure 6C). Experiment 2: the first reversal (i.e., SDRe) should serve to consolidate the formation of the attentional set challenged by the EDS stage (26),
whereas the second reversal (i.e., EDSRe) should serve as an internal control. This internal control will indicate if a deficiency in the EDS stage is related to
the previously acquired attentional set rather than impairment in learning a new reward association. The testing performance of mice showed a significant
effect for the number of trials (F3,48 ¼ 6.49; p ⬍ .001) and for the time needed to complete each stage (F3,48 ¼ 8.23; p ⬍ .0005). In particular, mice
improved their performance on the EDS stage because they needed fewer trials (p ⬍ .05; Figure 6D) and less time (p ⬍ .05; Figure 6E) to reach criteria in
the EDS compared with the SD and SDRe stages. Similar to the paradigm used in Experiment 1, these results suggest that mice did not reliably form an
attentional set for the previously relevant dimension (i.e., the visual cue) and that this task is not equivalent to primate tasks that are able to discern
attentional set-shifting abilities. However, analysis of the latency to make a nose-poke response showed a more convincing effect of discrimination (F3,48 ¼
4.30; p ⬍ .01). Even if the mice required fewer trials and less time to solve the EDS stage, they were slower in responding in the EDS compared with the
SD, SDRe, and EDSRe stages (p ⬍ .05; Figure 6F). These results suggest that increased time to respond in the EDS stage might indeed be a proxy measure
indicating the formation of an attentional set. *p ⬍ .05 and ***p ⬍ .0005 vs. previous stages.

nonhuman primates. The Operon paradigm can reliably measure The visual-cue/left-right response discrimination set-shifting
reversal learning, attentional set formation, and shifting, provid- procedure that has been previously proposed for rats (22) was
ing an effective new tool in the study of animal cognitive models not able to reliably measure set-shifting abilities in mice.
for translational medicine. Indeed, mice solved the shifting phase more easily than

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D. Scheggia et al. BIOL PSYCHIATRY 2013;]:]]]–]]] 9

previous stages, giving no evidence of attentional set forma-
tion. Even if this apparent EDS improvement was not found in
rats, normal PFC-functioning rats seemed not to show any set-
shifting impairment in this procedure (22). In contrast, the new
two-chamber ID/ED Operon task reliably measured attentional
set shifting as clearly demonstrated by poorer performance in
the EDS. This was confirmed using four cohorts of wild-type
mice and adopting two test paradigms (the two-dimension and
the more refined stuck-in-set). These findings are consistent
with previous studies in primates using the ID/ED task and in
rodents using the manual digging version (7,15,16). The
Experiment 3
1600 **
1200
Trials to criterion
attentional set shifting is identified as poor performance in
the EDS compared with previous stages. Additionally, we found
internal constructs that further validate the task: 1) a general
improvement from IDS to IDS2; 2) a specific improvement in
consecutive reversal stages, with the more within-set reversals
to which an animal is trained, the better it should perform on
subsequent within-set reversals (26); and 3) better performance
in the EDSRe compared with the EDS.
Our experiments demonstrated that the difficulty to solve the
EDS is also evident in the increase in response latencies. So far
this parameter has been mostly overlooked. However, in line with
our findings, a recent study in mice using the digging version of
the ID/ED task showed slower latencies to respond during the
EDS phase (35). Processing time increases to maintain optimal
accuracy during harder discriminations (36). Thus, considering the
latency to respond as an index of speed of information process-
ing, decision making, and problem solving (25), the slower
latencies during the EDS might reflect a strategy adopted to face
the difficulty in solving the set shifting.

The new paradigm was learned in each stage with an

equivalent number of trials irrespective of the relevant or
800 irrelevant dimension used (odor, texture, and light). This demon-
strated that the stimuli used have similar salience and are all
suitable for attentional set formation and/or shifting. Moreover,
400 this two-chamber Operon task presents the following advantages
over previously used ID/ED task for rodents: 1) it has less labor-
** intensive procedures, 2) it eliminates any source of subjectivity in
0 the measured parameters, 3) it eliminates any possibility that
SD SDRe SD SDRe EDS EDSRe mice might follow reinforcement-related cues to make a
repeated response, 4) it avoids arbitrary environmental conditions, and
5) it allows manipulation of three distinct dimensions with a large
range of different stimuli. Although we tested only mice, we
25 expect the same significant advantages of our novel task also for
testing rats.
Time to criterion (days)

20 We found that the genetic condition of reduced COMT activity,

which translates into increased cortical dopamine, produces a
15
selective improvement on EDS abilities, in line with human

Figure 7. Overtraining did not improve the automated visual-cue/left-

10 right response discrimination set-shifting procedure. Trials (A) and time
(B) needed to reach the criteria and latency to respond (C) during the
different stages of the task in Experiment 3. Note that here, compared
5 with Experiments 1 and 2, there was a repetition of simple discrimination
*** (SD) and SD reversal (SDRe) before the extradimensional shift (EDS) stage.
Moreover, in this experiment, there was no habituation phase, and more
0
SD SDRe SD SDRe EDS EDSRe stringent criteria were applied. Indeed, the more within-set reversals or
the more stringent the criteria with which the animal is trained, the better
repeated it should perform on subsequent within-set reversals and the worse it
should perform when presented with a set shift (14). Fourteen were
tested; 1 mouse was excluded because it was not able to finish the entire
0.08 procedure. The other mice readily learned to poke into the nose poke
holes and to discriminate the stimuli. An effect of discrimination was
present for trials (F5,65 ¼ 44.00; p ⬍ .0001) and time (F5,65 ¼ 27.59; p ⬍
Latency to respond (sec)

0.06 .0001) needed to reach the criterion. Mice required significantly less trials
* to solve the EDS compared with the SD, SDRe, and SD- and SDRe-repeated
stages (p ⬍ .005; Figure 7A) and fewer days to solve the EDS compared
with the SD and SDRe stages (p ⬍ .0005; Figure 7B). Moreover, mice
0.04 required more trials to acquire the first reversal stage compared with the
SD (p ⬍ .005; Figure 7A). These results indicate that these operant
procedures might be useful to study reversal learning but further confirm
0.02 that they are not able to reliably measure attentional set-shifting abilities.
Analysis of latency to respond showed again an effect of discrimination
(F5,65 ¼ 5.27; p ⬍ .0005). Similar to what we found in previous
experiments, mice were slower in responding in the EDS compared with
0 the previous SDRe and SD- and SDRe-repeated stages (p ⬍ .05; Figure 7C).
SD SDRe SD SDRe EDS EDSRe These data indicate a slower speed of processing during the shifting
repeated strategy phase. *p ⬍ .05, **p ⬍ .005, and ***p ⬍ .0005 vs. previous stages.

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10 BIOL PSYCHIATRY 2013;]:]]]–]]]
findings on the WCST and on the CANTAB ID/ED task (20,29,37).
This same result, using a manual digging version, has been
obtained by the pharmacologic inhibition of COMT in adult rats
produced by tolcapone, a selective and brain-penetrant COMT
inhibitor (38). Conversely, transgenic mice with relative increased
levels of COMT (COMT Val-tg) have a selective impairment in the
EDS (16). These findings constitute additional validation of our
novel ID/ED Operon task.
Surprisingly, partial COMT genetic reduction produced an
impairment of serial reversal learning. Consistent with previous
findings (16), reduced COMT did not affect initial reversal
acquisition (CDRe) but more specifically impaired serial reversal
learning (IDS2Re). Similarly, two human studies have shown that
genetic conditions of reduced COMT activity, determined by
COMT Met/Met genotype, lead to a disadvantage in performing
serial reversal tasks (39,40). In particular, serial reversal learning is
impaired after dopamine but not serotonin depletion in striatal
regions (41), whereas the serotonin system in the orbitofrontal
cortex might be more relevant to initial reversal learning (42).
Thus, our findings provide initial evidence for potential differ-
ences in neuronal mechanisms underlying initial and serial
reversal learning.
Chronic administration of PCP produced a selective impair-
ment of EDS. This is consistent with previous findings that have
reported marked deficits of set shifting in rats after chronic PCP
treatment using the manual digging version (30,31,33). PCP-
dependent selective deficits in the EDS stage might be due to
PFC hypofunctionality (43) and reduced PFC dopamine utilization
(44). It is important to note that PCP treatment has been used as
an animal model of schizophrenia (21). Indeed, patients with
schizophrenia show deficits in executive functions and particu-
larly in EDS phases (6). We also showed that PCP treatment
produced a generalized decrease in latency to respond. This
might be explained by the increased impulsive and compulsive
traits observed after repeated PCP administration (45). Overall,
this evidence demonstrates the effectiveness of our novel task in
revealing selective pharmacologically driven damages and that it
might be useful in the study of animal models of psychiatric
diseases.
In conclusion, this study supports the translational effec-
tiveness of the new Operon ID/ED task as a high-fidelity
preclinical tool. Indeed, it closely mimics the original tests
used in humans and is suitable in predicting the effects of
genetic modifications (i.e., COMT) and pharmacologic treat-
ments (i.e., PCP) that are known to alter specific facets of
cognitive control. The novel ID/ED Operon task produced
similar data to the already effective and well-validated manual
attentional set shifting digging version for rodents. However,
the novel and automated set up of our task make it more
suitable and feasible for large drug and/or genetic screenings
relevant to executive dysfunctions and cognitive symptoms of
psychiatric disorders.
This research was supported by the Istituto Italiano di Tecnolo-
gia, the Marie Curie FP7-Reintegration (Grant No. 268247), and the
Intramural Research Program of the National Institute of Mental
Health. The authors declare no biomedical financial interests or
potential conflicts of interest.
We thank K. Jenkins and G. Pruzzo for their excellent technical
assistance and the mechanical workshop of the Istituto Italiano
di Tecnologia for help building our new apparatus. We thank
Dr. S. Floresco for initial critical discussion on the cue–response
discrimination paradigm. We thank Dr. G. Carr and H. Huang for
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D. Scheggia et al.
proofreading the manuscript. We thank Drs. M. Karayiorgou and
J.A. Gogos for donating the COMT
/
mice breeders.
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