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The Journal of Neuroscience, June 1, 2000, 20(11):4320-4324
Medial Frontal Cortex Mediates Perceptual Attentional Set
Shifting in the Rat
Jennifer M.
Birrell and
Verity J.
Brown
School of Psychology, University of St. Andrews, St. Andrews KY16
9JU, Scotland, United Kingdom
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ABSTRACT |
If rodents do not display the behavioral complexity that is
subserved in primates by prefrontal cortex, then evolution of prefrontal cortex in the rat should be doubted. Primate prefrontal cortex has been shown to mediate shifts in attention between perceptual dimensions of complex stimuli. This study examined the possibility that
medial frontal cortex of the rat is involved in the shifting of
perceptual attentional set. We trained rats to perform an attentional set-shifting task that is formally the same as a task used in monkeys
and humans. Rats were trained to dig in bowls for a food reward. The
bowls were presented in pairs, only one of which was baited. The rat
had to select the bowl in which to dig by its odor, the medium that
filled the bowl, or the texture that covered its surface. In a single
session, rats performed a series of discriminations, including
reversals, an intradimensional shift, and an extradimensional shift.
Bilateral lesions by injection of ibotenic acid in medial frontal
cortex resulted in impairment in neither initial acquisition nor
reversal learning. We report here the same selective impairment in
shifting of attentional set in the rat as seen in primates with lesions
of prefrontal cortex. We conclude that medial frontal cortex of the rat
has functional similarity to primate lateral prefrontal cortex.
Key words:
attention; set shifting; prefrontal cortex; Cg3; prelimbic cortex; rat
| |
INTRODUCTION |
Whether there is a homolog of
primate prefrontal cortex on the medial wall of frontal cortex of the
rodent brain is an issue of continuing controversy (Kolb, 1990 ; Preuss,
1995). There are extensive projections from the mediodorsal nucleus of
the thalamus to medial frontal cortex and these projections are
generally assumed to define rodent prefrontal cortex. Nevertheless, in
primate, areas other than prefrontal cortex also receive projections
from mediodorsal nucleus (for example, anterior cingulate cortex). Thus, receipt of mediodorsal thalamic projections cannot be accepted as
evidence that an area of rodent cortex is homologous to primate prefrontal cortex as opposed to, for example, cingulate cortex (Preuss,
1995). An alternative approach to the issue is to consider the
function, rather than anatomy, of frontal areas. The evolution of
prefrontal cortex in the primate is, presumably, to support a degree of
behavioral complexity that might not be found in the rat. However, if
the rodent does demonstrate behavior dependent on functions associated
with primate prefrontal cortex, the neural substrate of such behavior
could be regarded as at least analogous, if not homologous, to primate
prefrontal cortex.
In primates, prefrontal cortex mediates shifts in attention between
perceptual features of complex stimuli (Owen et al., 1991; Dias
et al., 1996a,b, 1997). When attending to a perceptual feature (e.g., color) of a stimulus, learning to discriminate novel complex stimuli is more rapid when the discrimination rule is based on the same
perceptual dimension [an intra-dimensional (ID) shift]. By contrast,
if the new discrimination requires that attention is directed to a
different perceptual dimension (e.g., the form of the stimulus) and the
previously attended feature must be disregarded [an extra-dimensional
(ED) shift], the new discrimination is acquired less rapidly. Lesions
of primate lateral prefrontal cortex result in normal acquisition of
attentional set but impairment on the ED shift (Dias et al., 1996a,b,
1997).
Rats with lesions of medial frontal cortex are impaired in shifting
between response rules (Joel et al., 1997; Ragozzino et al., 1999a,b),
which may reflect an attentional set-shifting deficit. Attentional
deficits have also been proposed to account for impairments in reversal
learning of difficult to discriminate stimuli (Bussey et al., 1997) and
delayed response tasks (Delatour and Gisquet-Verrier, 1999). However, a
compelling demonstration of a deficit of attentional set-shifting would
be to show that medial frontal cortex lesions result in specific
deficits in shifting of selective attention for perceptual features of
stimuli. This would require a task that is formally the same as the
task used in humans and monkeys: a two-choice discrimination using
complex stimuli that differ along several perceptual dimensions. Here
we report the effects of lesions of rodent medial frontal cortex on
performance of such a task.
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MATERIALS AND METHODS |
Animals. Twenty-four Lister hooded rats (Charles
River, Margate, Kent, UK) were housed individually in 25 × 45 × 15 cm plastic cages. Testing was conducted in the light
phase of a 12 hr light/dark cycle (lights on at 7 A.M.). The
rats were maintained on a restricted diet (15-20 gm of food per day)
with water freely available in the home cage. We adhered to the
guidelines laid out in the Principles of Laboratory Animal
Care (National Institutes of Health, Publication No. 86-23, revised 1985) and the requirements of the United Kingdom Animals
(Scientific Procedures) Act 1986.
Apparatus. Rats can be trained to dig in small bowls filled
with sawdust to retrieve food reward (Wood et al., 1999). The digging
bowls used here were ceramic pots, with an internal diameter of 7 cm
and a depth of 4 cm. The bait was one-half of a Honey Nut Loop
(Kellogg, Manchester, UK). The outer surface and rim of the bowl
were covered with a texture, and the bowls were filled with a digging
medium, which could be scented. Thus, the bowls could be varied by
their odor, the texture of the outer surface and rim of the bowl, or
the digging medium in which the food bait was hidden.
The test apparatus was an adapted plastic cage (40 × 70 × 18 cm) with Plexiglas panels used to divide one-third of the length of
the cage into two sections. The digging bowls were placed in these
sections, with a central divider between them. A removable divider
separated the rat from the two sections in which the bowls were placed.
The rat could be given access to the bowls by lifting this divider. The
purpose of the dividers was to enable the experimenter to block access
to the bowls, particularly after an error; without the dividers, a rat
could move quickly between the bowls and retrieve the bait before the
experimenter had time to remove it.
Habituation. On the day before testing, rats were given
access to two sawdust-filled bowls in the testing cage for 60 min. Both
of the bowls were rebaited every 5 min. When the rat was reliably
digging to retrieve the rewards, it was trained on a series of three
simple discriminations (SDs) (texture of rubber vs masking tape; odor
of blackcurrant vs vanilla; digging medium of styrofoam vs shredded
paper) to a criterion of six consecutive correct trials. All rats were
trained on the same discriminations, in the same order. The exemplars
were not used again.
Testing paradigm. A trial was initiated by raising the
divider to give the rat access to the two digging bowls, only one of which was baited. The first four trials were discovery trials: the rat
was permitted to dig in both of the bowls, but only one was baited. An
error was recorded if the rat dug first in the unbaited bowl. On
subsequent trials, if the rat started to dig in the unbaited bowl, an
error was recorded, and the trial was terminated. Testing continued
until the rat reached a criterion level of performance of six
consecutive correct trials.
In a single test session, rats performed a series of discriminations
that paralleled those used in the equivalent task for primates (Table
1). In the SD, the bowls differed
along one of three dimensions (e.g., odor or texture or digging
medium). For the compound discrimination (CD), a second dimension was
introduced, but the correct and incorrect exemplars remained constant.
For the reversals (Rev1, Rev2, and Rev3), the exemplars and the
relevant dimension were unchanged: the rat had to learn that the
previously correct stimulus was now incorrect. For both the ID and ED
shifts, there were new exemplars of both the relevant and irrelevant
dimensions (a total change design); in the latter case, the previously
relevant dimension was now the irrelevant dimension. The order of the
discriminations was always the same, but the dimensions and the pairs
of exemplars were equally represented within groups and counterbalanced
between groups as far as possible.
There were six possible patterns of shift (odor to texture or medium,
medium to odor or texture, texture to medium or odor), so each pattern
of shift was used twice in each group. The combinations of exemplars
were too numerous to permit full counterbalancing; therefore, the
following procedure was used. To reduce the degrees of freedom,
exemplars were always used in pairs; for example, if cumin were the
positive stimulus, the negative stimulus was always cinnamon (Table
2). This also meant that exemplars of texture and digging medium could be matched for their odors and visual
appearance; thus, grades of tea were used as a pair of exemplars of
digging medium, and reverse sides of velvet cloth were used as a pair
of exemplars of texture. Although pairs were still too numerous to test
all combinations, no two rats within groups received the same
combinations, but the lesion and control groups were matched. The
combining of exemplars into stimuli and the side of stimulus
presentation were determined by an a priori pseudorandom
list.
Surgery. Anesthesia was induced with an intraperitoneal
injection of pentobarbitone sodium (1.0 ml/kg, 65 mg/ml). The rats were
then placed in a stereotaxic frame with atraumatic ear bars (Kopf,
Tujunga, CA), with the nose bar set at +5 mm. The ibotenic acid was
infused manually using a 1 µl syringe, at a rate of 0.1 µl every 3 min. Twelve rats each received four injections of 0.2 µl of 0.06 M ibotenic acid (Tocris Cookson, Avonmouth, UK),
bilaterally at the following coordinates relative to Bregma:
anteroposterior (AP) +3.5; mediolateral (ML) ±0.6; dorsoventral (DV)
 5.2; and AP +2.5; ML ±0.6; DV 5.0. Control rats received
infusions of vehicle at the same coordinates. The syringe was left in
place for 4 min before being withdrawn slowly. Testing was conducted on
day 5 after surgery.
Histology. The rats were killed by intraperitoneal
administration of Euthanol (1.0 ml/kg, pentobarbitone sodium, 200 mg/ml). The rats were perfused transcardially with phosphate buffer for 2 min at a rate of 10 ml/min, followed by a 4% paraformaldehyde in
phosphate buffer for 20 min at the same rate. The brains were removed
and placed into a 20% sucrose/4% paraformaldehyde phosphate buffer
solution until processed. Using a freezing microtome, 50 µm coronal
sections were saved every 400 µm for staining with cresyl violet.
Data analysis. Trials to criterion and errors to criterion
were recorded for each rat for each discrimination; however, because the two measures are correlated and analysis of either measure produced
the same results, only trials to criterion are reported. Repeated-measures ANOVA was used, with three factors, one
within-subjects (shift: SD, CD, Rev1, ID, Rev2, ED, Rev3) and
two between-subjects (group: lesion and control; dimension change: odor
to medium, odor to texture, medium to odor, medium to texture, texture
to odor, and texture to medium). Planned comparisons were performed to
test the source of significant interactions. Separate analyses were
performed on the discriminations before the ED shift (to test the
effect of initial dimension on acquisition) and the reversal discriminations (to compare initial acquisition and the three reversals).
| |
RESULTS |
Histology
Twelve rats sustained bilateral damage of medial frontal cortex.
Figure 1 is a series of coronal sections
(adapted from Paxinos and Watson, 1997) showing the area of damage that
was common to all rats as well as the areas common to 50% of rats. A
boundary of damage is shown, representing not the largest lesion but
the maximum extent of any lesion. Using the sections and nomenclature of Paxinos and Watson (1997), the lesions were centered on prelimbic cortex (PrL), but in all cases included damage to infralimbic cortex
(IL). In half of the rats, the lesions extended dorsally to include
anterior portions of cingulate cortex, Cg1 and Cg2. In two rats, there
was minor damage to anterior M2.
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Figure 1.
A series of coronal sections (adapted from Paxinos
and Watson, 1997) at 3.7, 2.7, and 1.0 mm anterior to bregma. The
extent of the area of damage common to all lesioned rats is shown in
black, whereas the area of damage common to 50% of rats
is shown shaded. The maximum extent of any damage is
shown as a dotted line.
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Discrimination learning
Figure 2 shows the trials to
criterion for each of the discriminations. On average, rats learned the
simple discrimination to the criterion of six correct consecutive
trials, in just eight trials. Analysis of the stages before the ED
shift confirmed that performance did not significantly differ within
the three perceptual dimensions (main effect of initial dimension,
F(2,18) = 1.12, NS).
There was no effect of the lesion on these initial stages (main effect
of group, F(1,18) = 0.95, NS; group by stage interaction, F(1,18) = 1.67, NS).
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Figure 2.
Bar graph showing number of trials to a criterion
(six consecutive correct trials) for each discrimination. ID shifts
were learned more rapidly than ED shifts. The lesions resulted in a
selective impairment in the ED shift; *p < 0.05 compared with control.
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Reversal learning
After the CD, ID, and ED stages, the correct and incorrect
exemplars were reversed. All rats required more trials to learn the
reversals than they required for either initial acquisition (SD and CD
stages) or the ID shift, also a novel discrimination (main effect of
reversal, F(1,22) = 92.5, p < 0.05). It was not possible to divide
performance into epochs corresponding to a period of perseverative
responding and a period of learning (Hunt and Aggleton, 1998), because
learning was so rapid. There was a mean of 5.4 trials preceding the six
criterion trials and a mean of 3.9 errors to criterion. Thus, most of
the trials were perseverative. There was no effect of the lesion on
reversal learning (interaction of group and reversal:
F(1,22) = 0.3, NS).
ID versus ED shifts
Learning a novel discrimination was faster when the discrimination
was based on the previously relevant perceptual dimension (an ID shift)
compared with an ED shift, when attention had to be shifted to the
previously irrelevant dimension. All rats performed ID shifts more
rapidly than ED shifts (planned contrast, ID vs ED, after main effect
of shift, F(1,12) = 89.49, p < 0.05), demonstrating that the rats formed a
perceptual attentional set. Each dimension change (i.e., odor to medium
or texture, medium to odor or texture, texture to odor or medium) was
equivalent with respect to the ease of shifting attentional set (main
effect of dimension change, F(5,12) = 1.31, NS).
Medial frontal cortex lesions resulted in a selective impairment in the
ED shift, with lesioned rats taking twice as many trials as controls to
learn the new discrimination (lesion by shift interaction,
F(6,72) = 3.48, p < 0.05; planned contrasts indicated the lesion effect was restricted to
the ED shift, F(1,12) = 7.2, p < 0.05).
| |
DISCUSSION |
Lesions of rat medial frontal cortex, centered on PrL and IL,
resulted in a selective impairment of an ED shift, with no impairment in acquisition or reversal learning. These results indicate that medial
frontal cortex contributes to extra-dimensional attentional set-shifting in the rat. Although half of the rats also had damage extending to Cg1-2, the presence of damage more dorsally was not associated with greater deficits.
Previous authors have demonstrated that rule-shifting is impaired in
rats with lesions of medial frontal cortex (Joel et al., 1997;
Ragozzino et al., 1999a,b). Although impaired shifting of attentional
set might result in a deficit in shifting response rule, it is not
necessarily the case that a deficit in shifting response rule must be
caused by an impairment of attentional set. This study extends previous
work in showing that lesions of medial frontal cortex result in
deficits in the shifting of perceptual set.
Validation of the test
An attentional set is formed when complex stimuli must be
classified or discriminated, to enhance the efficiency of processing of
currently relevant features of a stimulus and enable irrelevant differences between stimuli to be ignored. The class of attended or
ignored features is referred to as a stimulus dimension. This may be
some perceptual attribute of the stimulus (such as the color or the
shape of a visual object), but any other attribute by which stimuli may
be classified and discriminated is also a stimulus dimension (for
example, a semantic attribute, such as words and non-words). The
problem of demonstrating perceptual attentional set in animals is
designing an appropriate task. It is a challenge to devise stimuli with
species-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 (a total change design). Without a total
change design, the interpretation of the superiority of reversal
learning over ED shifts, as demonstrated by Mackintosh (1965),
is ambiguous (Slamecka, 1968). Thus, to test ID and ED shifts,
these requirements necessitate a minimum of two dimensions with six
exemplars of each dimension.
The dimensions must be species-appropriate, to achieve rapid learning
that is preferably equivalent for each dimension. Shepp and Eimas
(1964) found that rats took more than 1 week of 25 trials per day to
learn to discriminate visual stimuli by pattern or shape. Furthermore,
attending to the shape of a stimulus retarded a subsequent shift of
attention to its pattern more than was the case for the converse shift.
The particular dimensions we used (odor, texture, or digging medium)
were without differential effect on performance: at the CD stage of
testing, none of the newly introduced irrelevant dimensions exerted
greater distraction and neither was distractibility greater for any
particular relevant dimension. Furthermore, each type of ED shift (odor
to or from texture, medium to or from texture, and odor to or from
medium) was learned with an equivalent number of trials. This finding has implications for the use of odor stimuli in memory tasks. It might
be argued that odor stimuli are unsatisfactory because the rat may
"carry" the odor on its fur to a subsequent trial, so aiding
discrimination. However, the fact that the odor discrimination was not
learned more rapidly than texture or digging medium (neither of which
could easily be transferred to subsequent trials) suggests that rats do
not use this strategy, and thus odor discriminations are suitable for
use in memory tasks.
The task as used in humans and monkeys involves two dimensions that are
different visual features of the stimulus. This contrasts with our
task, which uses somatosensory and olfactory features of the stimulus.
In the marmoset, the two dimensions used are filled shapes versus
configurations of lines superimposed on the shapes. Obviously, these
are both shape discriminations. What makes them separate dimensions is
that they are stimulus features that are not related: shapes A and B
can be paired with either line 1 or line 2, and at any time only one
aspect of the pair (shape or line) is relevant. We considered the
possibility that the rat might discriminate the texture or the digging
medium by using visual or olfactory, rather than somatosensory, cues.
We tried to minimize this possibility by choosing pairs of exemplars of
texture with the same color and odor (reverse sides of dark velvet
cloth, for example). However, such a procedure is not actually necessary. If the rat is able to discriminate one of two textured bowls, and ignore another irrelevant feature that might be associated with either, it is not relevant to the procedure which sensory system
the rat is using. Furthermore, if this ability to discriminate the
bowls according to one feature retards the ability to learn to
discriminate the two bowls according to another feature, we can
conclude that an attentional set is formed. The contents of attentional
set transcend sensation and sensory modality.
Medial frontal lesions and reversal learning
Previous work has reported deficits in reversal learning after
lesions of medial frontal cortex (for review, see Kolb, 1990), but
Bussey et al. (1997) showed that reversal learning was only impaired
when the stimuli were difficult to discriminate. Bussey et al. (1997)
suggest that this reversal deficit might be caused by impairment in the
ability to attend to relevant stimulus features. Here, we replicate
their result that medial frontal lesions result in no impairment in
reversal learning of easily discriminable stimuli, and we provide
evidence to suggest that their deficit is indeed likely to be of one
selective attention.
Reversals are a special case of an intradimensional shift. Like the ID
shift, reversal learning does not require attention to be reoriented,
because the attended dimension remains the same. However, unlike the ID
shift in which all the exemplars are novel, in the reversal, the
exemplars remain the same: the previously correct exemplar is now
incorrect, and the rat must respond to the previously incorrect
exemplar. Any tendency to persevere in responding to a previously
correct stimulus would impair reversal learning. All rats required more
trials to learn the reversals than they required for either initial
acquisition (SD and CD stages) or an ID shift in which all the stimuli
were novel. However, there was no effect of the lesion of medial
frontal cortex on reversal learning. This indicates that the ED shift
deficit is not caused by a problem with perseverative responding in a
general sense, because the rats are as able as controls to abandon a
response to a previously reinforced stimulus. Rather, perseveration is restricted to the shifting of attention.
Medial frontal cortex lesions and set-shifting
All rats performed ID shifts more rapidly than ED shifts,
demonstrating that the rats formed a perceptual attentional set. The
rats with medial frontal cortex lesions showed retardation in the
shifting of attentional set, doubling the number of errors at this
shift. It should be noted that although the discrimination was learned
more slowly, it was not a more difficult discrimination: only previous
experience of attending to the now irrelevant dimension distinguished
the new learning at the ED shift from that at the ID stage. Therefore,
the lesion effect cannot be attributed to an effect of discrimination
difficulty, other than that resulting from the necessity to shift
attentional set.
The result we report here is directly comparable, in nature as well as
magnitude, to the set-shifting deficit reported in marmosets after
lesions of lateral frontal cortex (Dias et al., 1996a,b, 1997).
Consequently, this task provides the opportunity to study the
neuropsychological basis of attentional set-shifting in rats, which has
many practical advantages over primates. Because our task also includes
a third dimension, it will be possible in the future to examine the
nature of the deficit in terms of learned irrelevance and perseveration
(Owen et al., 1993; Gauntlett-Gilbert et al., 1999), which is
not possible in a task with just two dimensions.
Using this measure of perceptual attentional set-shifting in the rat,
the work reported here provides compelling evidence to support what has
already been suggested in the literature. Namely, that rat medial
frontal cortex is not merely concerned with spatial tasks or working
memory function, but rather, that the deficits reflect impairment of a
supervisory attentional system (Bussey et al., 1997). This suggests
that rat medial frontal cortex contains a homolog of primate prefrontal
cortex. Furthermore, this study has developed a suitable task for use
in the rat, so that investigations into the neural basis of perceptual
attentional set need no longer be restricted to primates.
| |
FOOTNOTES |
Received Jan. 24, 2000; revised March 13, 2000; accepted March 20, 2000.
This work was supported by The Wellcome Trust (Project Grant
051945/Z/97/Z). J.B. received a Biotechnology and Biological Sciences
Research Council (UK) studentship. We thank the animal care
staff of the School of Psychology Animal House; Andrew Blackwell, Dr.
Janice Phillips, and William Robb for assistance during the development
of the behavioral task; and Dr. Angela C. Roberts for helpful discussion.
Correspondence should be addressed to Dr. Verity J. Brown, School of
Psychology, University of St. Andrews, St. Andrews KY16 9JU, Scotland,
UK. E-mail: vjb{at}st-and.ac.uk.
| |
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F. Passetti, Y. Chudasama, and T. W. Robbins
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M. D. Barense, M. T. Fox, and M. G. Baxter
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TOP
ABSTRACT
INTRODUCTION
