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The Journal of Neuroscience, February 15, 1998, 18(4):1613-1621
D1 Receptor Modulation of Hippocampal-Prefrontal
Cortical Circuits Integrating Spatial Memory with Executive
Functions in the Rat
Jeremy K.
Seamans,
Stan B.
Floresco, and
Anthony G.
Phillips
Department of Psychology, University of British Columbia,
Vancouver, British Columbia, Canada V6T 1Z4
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ABSTRACT |
Dopamine (DA) within the prefrontal cortex (PFC) plays an important
role in modulating the short-term retention of information during
working memory tasks. In contrast, little is known about the role of DA
in modulating other executive aspects of working memory such as the use
of short-term memory to guide action. The present study examined the
effects of D1 and D2 receptor blockade in the
PFC on foraging by rats on a radial arm maze under two task conditions:
(1) a delayed task in which spatial information acquired during a
training phase was used 30 min later to guide prospective responses,
and (2) a nondelayed task that was identical to the test phase of the
delayed task but lacked a training phase, thereby depriving rats of
previous information about the location of food on the maze. In
experiment 1, microinjections of the D1 antagonist
SCH-23390 (0.05, 0.5, or 5 µg/µl), but not the D2
anatagonist sulpiride (0.05, 0.5, or 5 µg/µl), into the prelimbic
region of the PFC before the test phase disrupted performance of the
delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study,
we also investigated the role of D1 receptors in modulating activity in hippocampal-PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability
to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 receptor activation in the PFC and D1 receptor modulation of
hippocampal inputs to the PFC. These data suggest that D1
receptors in the PFC are involved in working memory processes other
than just the short-term active retention of information and also
provide direct evidence for DA modulation of limbic-PFC circuits
during behavior.
Key words:
prefrontal cortex; hippocampal formation; dopamine; memory; foraging; radial maze
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INTRODUCTION |
The prefrontal cortex is involved in
the ability to retain and use mnemonic information to guide action
(see, for example, Funahashi and Kubota, 1995 ; Goldman-Rakic, 1995;
Seamans et al., 1995). Neurons recorded from the prefrontal cortex
(PFC) of behaving primates (Fuster, 1995; Goldman-Rakic, 1995, 1990)
and rats (Orlov et al., 1988; Batuev et al., 1990) show sustained
firing throughout the brief delay period of a delayed-response task,
which is thought to provide an internal representation of previously
presented stimuli. Likewise, imaging data from human subjects suggest
that the PFC is involved in the active maintenance of information in a
short-term memory store (Cohen et al., 1997; Courtney et al., 1997).
The integrity of the active short-term memory trace within the PFC
appears to be regulated by the activity of a dopamine (DA) system,
because destruction of DA terminals in the PFC disrupts performance on
delayed-response or delayed-alternation tasks (Brozoski et al., 1979;
Bubser and Schmidt, 1990), whereas the administration of high doses of
D1, but not D2, antagonists into
the PFC also impair performance on delayed-response tasks and decrease
delay-period activity of PFC neurons (Sawaguchi et al., 1990b;
Sawaguchi and Goldman-Rakic, 1994; Williams and Goldman-Rakic, 1995;
Zahrt et al., 1997). Moreover, iontophoresis of low doses of
D1 antagonists or DA into the PFC increases
delay-correlated activity of PFC neurons relative to background
activity (Sawaguchi et al., 1988; Sawaguchi et al., 1990a; Williams and
Goldman-Rakic, 1995). Thus, too much or too little DA may be
detrimental to cognition. These data clearly indicate a role for DA
modulation of neural processes within the PFC related to the short-term
active retention of information.
In addition to active retention of information over very short delays,
the PFC, in collaboration with a variety cortical and subcortical
regions, is also involved in the ability to use mnemonic information to
plan a sequence of forthcoming responses (Shallice, 1982; Robbins,
1996; Shallice and Burgess, 1996; Floresco et al., 1997). Indeed,
Fuster (1993) has stated that frontal lobes are involved primarily in
memory for action. This type of memory for action embodies the concept
of working memory as defined by Baddeley (1986) because it emphasizes
the executive control of memory to guide action. We have used a
modified delayed-response task, termed the delayed spatial win-shift
task in rats, specifically to investigate this component of working
memory. During the training phase of the delayed spatial win-shift
task, the rat acquires trial-unique spatial information that must be
retained for use at a later time. During the subsequent test phase,
this information must be retrieved and integrated into a prospective
search strategy if the rat is to retrieve four food pellets efficiently
from eight possible locations on a radial-arm maze. Efficient
performance on this task (i.e., visiting only arms that contain food)
can be achieved only if the rat has acquired, and can use, spatial
information regarding the probable location of food on the maze.
Lidocaine inactivations of the medial PFC before the training phase of
the delayed task did not affect training phase performance, or memory for the location of food in the subsequent test phase, at a time when
the anesthetic effects of lidocaine had dissipated. In contrast, reversible inactivations just before the test phase severely impaired the rats' ability to use mnemonic information about the probable location of food to plan forthcoming foraging behaviors (Seamans et
al., 1995). Subsequent results suggested that spatial information may
be retained in the hippocampus over the 30 min delay and accessed by
the PFC when it is required to plan an efficient sequence of foraging
responses (Floresco et al., 1997). At present, it is not known whether
this component of working memory is also influenced by DA in the
PFC.
DA has multiple actions on PFC neurons as studied in vivo
and in vitro. Local application of DA inhibits spontaneous
activity within the PFC (Ferron et al., 1984; Mantz et al., 1988; Pirot et al., 1992), and this effect appears to be mediated indirectly via
the action of DA on local interneurons, because it is occluded by
pretreatment of a GABA antagonist (Pirot et al., 1992). Direct application of DA (but not VTA stimulation) enhances both excitatory responses and synaptic plasticity in the hippocampal-PFC pathway (Jay
et al., 1995, 1996). Moreover, as noted above, iontophoresis of DA into
the PFC of behaving primates enhances delay-period activity
significantly more than background or non-task-correlated activity
(Sawaguchi et al., 1990a). Collectively, these data suggest that DA may
act to enhance functional inputs to PFC neurons from regions such as
the hippocampus. Anatomical data indicate that DA and hippocampal
terminals often are found in close proximity to each another on layer V
PFC neurons (Carr and Sesack, 1996). We hypothesize that local blockade
of DA receptors will disrupt the selective augmentation of hippocampal
inputs to PFC neurons and, as a consequence, impair behaviors dependent
on the integrity of the hippocampal-PFC pathway.
In the present study, we examined the effects of D1 and
D2 receptor blockade in the PFC on delayed and nondelayed
radial-arm-maze foraging (Seamans and Phillips, 1994; Seamans et al.,
1995). We also investigated whether endogenous DA activity within the
PFC specifically modulated hippocampal afferents during the performance of the delayed task. To this end, we used a modified version of the
transient disconnection procedure. In the standard transient disconnection procedure (Floresco et al., 1997), unilateral lidocaine injections were delivered to the origin of the hippocampal-PFC pathway
in the ventral CA1/subiculum (vSub) and the termination of this pathway
in the contralateral prelimbic (PL) region of the medial PFC (Jay and
Witter, 1991; Condé et al., 1995). This procedure caused a
selective disruption of delayed-response performance, whereas
unilateral injections into either site had no effect on working memory
(Floresco et al., 1997). In the present study, we substituted an
injection of the D1 antagonist SCH-23390 for the
nonspecific lidocaine injection into the PL. A critical role for
D1 receptors in the PFC would be revealed if task
performance was disrupted selectively by the combination of the
D1 antagonist in the PL and lidocaine in the vSub.
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MATERIALS AND METHODS |
Subjects
The subjects were male Long-Evans rats weighing between 300 and
450 gm before surgery. All rats were given free access to water and
were maintained at 85% of their free-feeding weight by providing 25 to
30 gm of Purina lab chow pellets once daily. Rats were tested 5 to 7 d/week.
Surgery
Rats were anesthetized with 100 mg/kg ketamine hydrochloride and
7 mg/kg xylazine. Twenty-three-gauge stainless steel guide cannulae
were implanted into the brain regions using standard stereotaxic
techniques. The stereotaxic coordinates (flat skull) were derived from
Paxinos and Watson (1986). Cannulae were implanted bilaterally into the
PL (AP +2.6 mm, ML ±0.7 mm from bregma, DV  3.0 mm from dura) alone
or in combination with bilateral cannulae implanted into the vSub
region of the hippocampus (AP 6.0 mm from bregma, ML ±5.5 mm from
midline, DV 5.3 ± 0.3 mm from dura). This region of the
hippocampus was chosen because it sends dense projections to the PL
region of the PFC in the rat (Jay et al., 1991; Condé et al.,
1995). Thirty-gauge obdurators flush with the end of the guide cannulae
remained in place until the injections were made. Each rat was given at
least 7 d to recover from surgery before testing.
Microinfusion procedure
On injection days, the obdurators were removed and 30-gauge
stainless steel injection cannulae were inserted 0.8 mm beyond the tip
of the guide cannulae. In experiment 1, the D1 antagonist SCH-23390 (0.05, 0.5, or 5 µg in 0.5 µl dissolved in physiological saline), the D2 antagonist sulpiride (0.05, 0.5, or 5 µg
in 0.5 µl dissolved with a drop of NaOH in PBS) (Research
Biochemicals), or vehicle injections were delivered at a rate of 0.5 µl/1.2 min by a microsyringe pump (Sage Instruments Model 341). In
experiment 2, SCH-23390 (0.5 µl/µg) or vehicle injections were made
unilaterally into the PFC while lidocaine (20 µg in 0.5 µl of
saline, Astra Pharmaceuticals or Research Biochemicals) or saline (0.5 µl) was delivered to the contralateral vSub. Injection cannulae were
left in place for an additional 1 min after each injection to allow for
diffusion. All SCH-23390, sulpiride, and corresponding vehicle injections were made 15 min before testing to ensure an optimal blockade of DA receptors (Sawaguchi and Goldman-Rakic, 1994). Lidocaine
and corresponding vehicle injections were made 5 min before testing.
Similar doses of D1 and D2 receptor antagonists have been used previously and are effective in disrupting working memory performance (Sawaguchi and Goldman-Rakic, 1994; Broersen et al.,
1995a,b).
Apparatus
An eight-arm radial maze was used for all experiments. The maze
had an octagonal center platform 40 cm in diameter connected to eight,
equally spaced arms, each measuring 50 cm × 9 cm, with a
cylindrical food cup at the end. Removable pieces of white opaque plastic (9 cm × 13 cm) were used to block the arms of the maze. The maze was elevated 40 cm from the floor and was surrounded by
numerous extra maze cues (i.e., cupboards, posters, doors, the
experimenter, etc.) in a room 4 m × 5 m × 3 m, which
was illuminated with overhead fluorescent lights (100 W).
Foraging tasks
The two foraging tasks used in the present study were the
delayed spatial win-shift (SWSh) and the nondelayed random foraging (RF) tasks.
Delayed SWSh task. This task was adapted from Packard et al.
(1990) and has been described in detail elsewhere (Seamans and Phillips, 1994; Seamans et al., 1995). On the first 2 d of
testing, rats were habituated to the maze environment. Subsequent
training trials were given once daily. These trials consisted of a
training phase and a test phase separated by a delay. Before the
training phase, a set of four arms was chosen randomly and blocked. In both the delayed SWSh task and the RF task, a novel set of arms was
chosen each day. Food pellets (Bioserv) were placed in the food cups of
the four remaining open arms. During the training phase, each rat was
given 5 min to retrieve the pellets from the four open arms and then
was returned to its home cage for the delay period (see below). During
the test phase of each daily trial, all arms were open but only the
arms that were blocked previously contained food. Rats were allowed a
maximum of 5 min to retrieve the four pellets during the test
phase.
The initial delay between training and test phases was 5 min. After
achieving criterion performance in which all four pellets were
retrieved in five or fewer choices during the test phase for 2 consecutive days, the delay was increased to 30 min. A 30 min delay was
used in previous studies because lidocaine injections could be
delivered before the training phase or during the delay period while
allowing sufficient time for the anesthestic effects to dissipate
before the test phase (Seamans and Phillips, 1994; Seamans et al.,
1995). In the present study, the first intracranial injections were
administered after attaining 2 consecutive days of criterion
performance at a 30 min delay. After the first injection day, animals
were again retrained to the criterion performance. The next day, a
second intracranial injection was administered. This procedure was
repeated until an animal had received the designated sequence of
injections, according to the protocols described below (see Design and
Procedure).
On injection days, the number and order of arm entries were recorded.
An arm entry was recorded when a rat moved down the entire length of an
arm and reached the food cup at the end of the arm. Errors were scored
as entries into nonbaited arms and further broken down into two error
subtypes. An across-phase error was defined as any initial
entry into an arm that had been visited previously during the training
phase. A within-phase error was any reentry into an arm that
had been entered earlier during the test phase. The latencies to reach
the food cup of the first arm visited and to complete the phase also
were recorded.
Nondelayed RF task. This task also has been described
elsewhere (Seamans and Phillips, 1994; Seamans et al., 1995).
Habituation to the maze during the first 2 days of training was
identical to the delayed SWSh procedure described above. On subsequent
daily trials, animals were required to forage for pellets placed at random in the food cups of four of the eight arms (hence the term "random foraging"). A novel set of arms was baited each day.
Animals were trained to a criterion of no more than one reentry error per trial for 4 consecutive days. The day after criterion performance was achieved, the first intracranial injections were administered. After the first injection day, animals were retrained to criterion for
2 consecutive days. As with the delayed SWSh task, this procedure was
repeated until each animal had received all of the designated injections.
Errors were scored as reentries into arms visited previously within a
trial. These errors were broken down further into reentries into baited
arms (arms that had been baited at the start of the trial) and
reentries to nonbaited arms (arms that were not baited before the start
of the trial). The number of reentries errors made on each of the
injection days was recorded and used for data analysis. As with the
delayed SWSh paradigm, the latencies to reach the first food cup
(either baited or nonbaited) after being placed on the maze and the
time required to retrieve all four pellets were also recorded.
Design and procedures
Experiment 1: bilateral injections of SCH-23390 or
sulpiride into the PL. A within-subjects design was used for all
four parts of experiment 1. Four groups of rats with cannulae implanted
bilaterally into the PL were trained on either the delayed SWSh task or
the RF task. Rats in group 1 received bilateral infusions of either SCH-23390 or vehicle into the PL in a counterbalanced order before the
test phase of the delayed SWSh task. Rats in group 2 received bilateral
infusions of either sulpiride or vehicle into the PL in a
counterbalanced order before the test phase of the delayed SWSh task.
Rats in group 3 received bilateral infusions of either SCH-23390 or
vehicle into the PL in a counterbalanced order before a daily trial of
the nondelayed RF task. Rats in group 4 received bilateral infusions of
either sulpiride or vehicle into the PL in a counterbalanced order
before a daily trial of the nondelayed RF task. After the first
infusion, each subsequent infusion was administered when the rats
reattained criterion performance for 2 consecutive days. The order of
injections was counterbalanced between rats using a quasi-Latin square
design.
Experiment 2: unilateral injections of SCH-23390 into the PL
combined with lidocaine inactivation of the contralateral vSub. In
experiment 2, we used a modified version of a transient disconnection procedure (Floresco et al., 1997), in which unilateral injections of
the D1 antagonist SCH-23390 were substituted for the
nonspecific neural blocker lidocaine. A within-subjects design was used
for this experiment. Well trained rats received a total of four
injections before the test phase of the delayed SWSh task. We used the
following combinations of asymmetrical unilateral injections: (1) a
unilateral inactivation of the vSub in combination with a contralateral
injection of SCH-23390 into the PL; (2) a unilateral inactivation of
the vSub in combination with a vehicle injection into the contralateral PL; (3) a unilateral injection of SCH-23390 into the PL and a vehicle
injection into the contralateral vSub; and (4) injections of vehicle
into the vSub and contralateral PL. The order of injections was
counterbalanced between animals using a quasi-Latin square design. The
counterbalancing ensured that a given sequence of injections was not
repeated. The hemisphere (left or right) used for the first injection
was also counterbalanced and was alternated for subsequent injections.
The injection procedure was repeated until the animal had received all
four combinations.
Histology
After completion of behavioral testing, the rats were killed in
a CO2 chamber. Brains were removed and fixed in a 10%
formalin solution. The brains were frozen and sliced in 50 µm
sections before being mounted. Placements were verified with reference to the neuroanatomical findings of Jay and Witter (1991), Condé et al. (1995), and Paxinos and Watson (1986).
Data analysis
The number and type of errors made on the day before the first
injection sequence and for all injection days for each experiment were
analyzed using separate two-way, between/within, mixed design ANOVAs
with the injection order as a between-subjects factor and treatment day
as a within-subjects factor. Main effects of treatment were analyzed
further using Tukey's post hoc tests for repeated measures.
Whenever a significant main effect of treatment was observed, a planned
comparison was performed that analyzed the number of each type of error
made on drug injection days.
The latency data to reach the first food cup and the average time per
subsequent choice on injection days were analyzed with a one-way
repeated-measures ANOVA. The average time per subsequent choice was
calculated using the following formula: [(time to complete trial time to initiate trial)  number of choices for trial].
Whenever a significant main effect of treatment was observed in
experiment 2, three one-way ANOVAs were conducted assessing the number
of errors made on injection days, with the side of the injection as a
between-subjects factor. This analysis was conducted to rule out the
possibility that unilateral inactivations in one hemisphere would lead
to a greater increase in errors than inactivations of the other
hemisphere.
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RESULTS |
Experiment 1: bilateral injections of SCH-23390 or sulpiride into
the PL
Histology
The location of the cannulae tips for all animals receiving
bilateral SCH-23390 injections into the PL before the delayed SWSh task
of experiment 1 are shown in Figure 1.
Placements were similar for the other groups in experiments 1 and 2. Data from animals the placements of which were not located in the PL
region of the PFC were not included in the data analysis.
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Figure 1.
Schematic representation of the SCH-23390
injection sites for rats in experiment 1. Black dots
represent the location of cannula tips. Illustrated brain sections are
computer-generated adaptations from Paxinos and Watson (1997).
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Delayed SWSh task. SCH-23390. Before the test
phase of the delayed SWSh task, seven rats received bilateral
counterbalanced infusions into the PL of vehicle and three doses of
SCH-23390 (0.05, 0.5, or 5 µg in 0.5 µl of vehicle) on separate
days. Analyses of the number of errors made on vehicle and all drug
injection days revealed a significant main effect of Treatment
(F3,18 = 4.96, p < 0.05; see
Fig. 2A). Tukey's
post hoc analysis for repeated measures showed that rats
made significantly more errors after injections of 0.5 and 5.0 µg of
SCH-23390 compared with vehicle and 0.05 µg SCH-23390 treatments
(p < 0.05). Subsequent planned comparisons on
the type of errors made on SCH-23390 injection days revealed that,
after injections of either 0.5 or 5.0 µg of SCH-23390 into the PL, an
equal number of across- and within-phase errors were made [all
F < 2.0, not significant (n.s.)]. There were no
significant effects of Injection Order or Treatment × Order
interactions (all F < 1.8, n.s.).
Sulpiride. Before the test phase of the delayed SWSh task,
seven rats received bilateral counterbalanced infusions of either
vehicle or three doses of sulpiride (0.05, 0.5, or 5 µg in 0.5 µl
of vehicle) into the PL on separate days. Analyses of the number of
errors made on vehicle and all drug injection days revealed no
significant main effect of Treatment (F3,18 = 1.62, n.s; see Fig. 2B). There were also no
significant effects of Injection Order or Treatment × Order interactions (all F < 1.8, n.s.).
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Figure 2.
The effects of bilateral injections of
D1 or D2 antagonists into the PL on performance
of the delayed SWSh task. A, Number of errors (mean ± SEM) made during the test phase by rats receiving saline
(hatched bar): 0.05, 0.5, and 5 µg of SCH-23390
(black bars) into the PL. B, Number of
errors (mean ± SEM) made during the test phase by rats receiving
PBS (hatched bar): 0.05, 0.5, and 5 µg of sulpiride
(black bars) into the PL. *p < 0.05 compared with saline injections.
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Nondelayed RF task. SCH-23390. Before a
daily trial of the nondelayed RF task, seven rats received
counterbalanced bilateral infusions of either vehicle or SCH-23390
(0.05, 0.5, or 5 µg in 0.5 µl of vehicle) into the PL on separate
days. Analysis of these data revealed no significant main effect of
Treatment (F3,18 = 2,27, n.s.; see Fig.
3A). There also were no
significant effects of Order of injection or Order × Treatment
interactions (all F < 2.3, n.s.).
Sulpiride. Before a daily trial of the nondelayed RF task,
seven rats received bilateral counterbalanced infusions of either
vehicle or sulpiride (0.05, 0.5, or 5 µg in 0.5 µl of vehicle) into
the PL on separate days. Analysis of these data revealed no significant
main effect of Treatment (F3,18 = 0.56, n.s.;
see Fig. 3B). There also were no significant effects of
Order of injection or Order × Treatment interactions (all
F < 0.7, n.s.).
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Figure 3.
The effects of bilateral injections of
D1 or D2 antagonists into the PL on performance
of the nondelayed RF task. A, Number of errors
(mean ± SEM) made during the nondelayed RF task by rats receiving
saline (hatched bar): 0.05, 0.5, and 5 µg of SCH-23390 (black bars) into the PL. B, Number of
errors (mean ± SEM) made during the nondelayed RF task by rats
receiving PBS (hatched bar): 0.05, 0.5, and 5 µg of
sulpiride (black bars) into the PL.
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Experiment 2: unilateral injection of SCH-23390 into the PL
combined with inactivation of the contralateral vSub
In experiment 2, a group of 7 rats with two sets of bilateral
cannulae implanted into the PL and the vSub received the injection protocol described above, before the test phase of the delayed SWSh
task, on four occasions. Statistical analyses revealed a highly
significant main effect of Treatment (F3,18 = 9.720, p < 0.001; see Fig.
4A). Tukey's
post hoc analysis for repeated measures revealed that rats
made significantly more errors when unilateral infusions of SCH-23390
into the PL were paired with contralateral infusions of lidocaine into
the vSub (p < 0.001). There were no other
significant differences in the number of errors made on any of the
other injection days. Subsequent planned comparisons on the type of
errors made after unilateral PL infusion of SCH-23390 and contralateral
vSub inactivations showed that rats made an identical number of across-
and within-phase errors (F1,6 = 0.0, n.s.; see
Fig. 4A, inset). Furthermore, there were
no significant effects of Injection Order, Error type, or any
significant interactions (all F < 1.4, n.s.).
Collectively, these results showed that D1 receptors
selectively modulate hippocampal afferents to the PL during the
performance of a long-delay SWSh task.
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Figure 4.
The effects of unilateral inactivation of the vSub
in combination with unilateral injections of SCH-23390 into the PL of
the contralateral hemisphere. A, Number of errors
(mean ± SEM) made during the delayed SWSh task by rats on the day
before the first injection (open bar), after unilateral
infusions of saline into both the PL and vSub (hatched
bar), unilateral infusions of SCH-23390 (SCH,
0.5 µg) into the PL and contralateral infusions of saline into the
vSub (gray bar), unilateral infusions of saline
into the PL and contralateral infusions of lidocaine into the vSub (vertical stripe bar), and unilateral injections of
SCH-23390 (SCH, 0.5 µg) into the PL and contralateral
injections of lidocaine into the vSub (black bar).
**p < 0.01 versus all other treatment conditions.
Inset shows the number of across-phase
(cross-hatched bar) and within-phase
(horizontal-striped bar) errors made by rats after the SCH/lidocaine injection condition. B,
Schematic representation of the SCH-23390 injection sites into the PL
and lidocaine injection sites into the vSub for rats in the
SCH/lidocaine condition. Black dots represent the
location of cannula tips. Illustrated brain sections are
computer-generated adaptations from Paxinos and Watson (1997).
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A separate series of tests revealed no evidence of hemispheric biases
on the number of errors made after unilateral vSub inactivations or
unilateral SCH-23390 injections into the PL (all F < 0.7, n.s.). However, rats that received unilateral inactivations of the
right vSub made significantly more errors than those rats that received left vSub inactivations (F1,5 = 7.10, p < 0.05). This effect was not observed previously
after identical unilateral vSub lidocaine injections (Floresco et al.,
1997). Given the large number of comparisons made in the present study,
this increase in errors after right unilateral vSub inactivations is
likely to be a spurious finding. Moreover, the total number of errors
made by rats after unilateral vSub inactivations, combined for both
hemispheres, did not differ significantly from other control
treatments.
Histology
The locations of the cannulae tips for all animals in experiment 2 are represented in Figure 4B. Bilateral placements in
the vSub were similar to those observed by Floresco et al. (1997). Similarly, bilateral placements in the PL were within the same region
of the PFC as those observed in experiment 1.
Analysis of response latencies
The latency data for both experiments 1 and 2 are presented in
Table 1. The latency data for each phase
of experiments 1 and 2 were analyzed separately. These analyses
revealed that none of the drug treatments in experiment 1 significantly
affected the latency to initiate the trial or the average time per
subsequent choice (all F < 1.5, n.s.). In experiment
2, SCH-23390 PFC microinjections paired with vehicle injections into
the vSub significantly reduced initiation times
(p < 0.05). Because neither bilateral SCH-23390 injections nor unilateral vSub vehicle injections affected response latencies in the other conditions, this anomolous result may not be a
real effect.
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DISCUSSION |
Our research showed that microinjection of a D1 but
not a D2 antagonist into the PL region of the PFC produced
a dose-dependent impairment on a delayed-foraging task. This indicated
that D1 receptor blockade in the PFC impaired the process
by which spatial information acquired 30 min earlier is used to guide
forthcoming approach responses. From the results of experiment 2, it
can be inferred that D1 receptors modulate hippocampal
inputs to the PFC during performance of a spatially mediated
working-memory task with a relatively long delay. These data complement
and extend previous reports that application of a D1
antagonist into the PFC in primates disrupts the active retention of
information during a brief delay (<6 sec) in an occulomotor
delayed-response task (Sawaguchi and Goldman-Rakic, 1994; Williams and
Goldman-Rakic, 1995). Taken together, these studies indicate that
D1 receptors modulate several different aspects of working
memory function in the PFC.
Our results demonstrate that D1 but not D2
receptors in the PL modulate delayed responding on the delayed task.
These data are consistent with those of Bubser and Schmidt (1990), who
showed that 6-OHDA lesions of the rat PL selectively impaired delayed but not spontaneous alternation on a T-maze. Furthermore,
D1 receptor blockade in the PFC of primates or rats
produces deficits on delayed-response tasks but typically not those
without a delay component (Sawaguchi et al., 1990b; Sawaguchi and
Goldman-Rakic, 1994; Broersen et al., 1995b; Williams and
Goldman-Rakic, 1995). Enhanced DA activity in the PFC also disrupts
delayed responding in rats, as shown by impaired performance of delayed
alternation on a T-maze after pharmacologically induced high rates of
DA turnover in the PFC or administration of D1 agonists
into the PFC (Murphy et al., 1996a,b; Arnsten, 1997; Zahrt et al.,
1997). These data indicate that maintenance of D1 activity
in the PFC within an optimal range is essential for working memory.
Although D2 receptor blockade in the PFC has been reported
to affect certain memory tasks in rats (Bushnell and Levin, 1983), most
studies have not found an effect of D2 antagonists on
delayed responding (Sawaguchi et al., 1990b; Sawaguchi and
Goldman-Rakic, 1994; Broersen et al., 1995b). There are a greater
number of D1 receptors compared with D2
receptors in the PFC (Farde et al., 1987; Gaspar et al., 1995), and
D1 receptor agonists have more clearly observed effects on
the firing properties of PFC neurons recorded in vitro (Yang
and Seamans, 1996). However, it has been suggested that D2
receptor modulation may play a more prominent role in older animals
(Arnsten et al., 1995).
Microinjections of the D1 receptor antagonist had no effect
on response initiation or on the average time per choice. This is
consistent with the observation of Broensen et al. (1995a,b) that
response latencies on the choice component of a delayed
nonmatching-to-position task were unaffected after bilateral injections
of similar doses of SCH-23390 into the rat PL. The fact that
D1 antagonists produced dissociable effects on the use of
previously acquired spatial information to guide subsequent responding
as opposed to any direct effects on response generation is consistent
with the suggestion that a planned series of responses generated in the
PFC must be relayed to other brain regions, such as the striatum for
translation into action (Robbins, 1991; Seamans et al., 1995; Floresco
et al., 1997). Furthermore, the deficit observed in this study after microinjections of a D1 antagonist into the PL was specific
to performance of the delayed task, because similar injections had no
effect on foraging during the nondelayed single-trial procedure. This
indicated that SCH-23390 injections did not affect either the ability
of the rats to navigate in a spatial environment or basic motivational
processes.
Spatially mediated foraging appears to be critically dependent on the
PFC and reciprocal interactions with the hippocampus (Floresco et al.,
1997). Experiment 2 demonstrated that D1 receptor blockade
in the PL coupled with inactivation of the vSub in the contralateral
hemisphere disrupted performance on the delayed foraging task. In this
context, it is important to emphasize that unilateral injection of
SCH-23390 in the PL in combination with vehicle injections into the
vSub had no effect on memory for the location of food. In our previous
"disconnection" study, we used asymmetrical injections of lidocaine
into both the PL and the vSub to demonstrate a critical role for a
hippocampal-PFC circuit in the working-memory function that enabled
rats to anticipate the location of food in complex environment
(Floresco et al., 1997). The logic underlying the use of this
disconnection procedure to identify components of a functional neural
circuit is based on the assumption that information is transferred
serially from one structure to an efferent region, on both sides of the
brain in parallel. Furthermore, the design assumes that dysfunction will result from blockade of neural activity at the origin of a pathway
in one hemisphere and the termination of the efferent pathway in the
contralateral hemisphere. The fact that blockade of D1
receptors in the PL in one hemisphere disrupted delayed foraging when
combined with a reversible lesion of the vSub is consistent with an
important gating function for D1 receptors during the
transmission of information in a hippocampal-PFC circuit.
A circuit for working memory
It has been proposed that short-term retention of visuo-spatial
information and executive functions are components of working memory
(Baddeley and Hitch, 1974; Baddeley and Della Sala, 1996). Evidence for
a role of the PFC in the former component of working memory comes from
recording studies in nonhuman primates showing that PFC neurons encode
and retain actively information about previously presented
visuo-spatial information over brief delays (Funahashi et al., 1989;
Goldman-Rakic, 1995; Miller et al., 1996). In humans, PFC activation is
also observed during the active retention of information on a
working-memory task (Cohen et al., 1997). The executive component of
working memory is hypothesized to coordinate and manipulate
visuo-spatial information (Baddeley and Hitch, 1974; Baddeley, 1986;
Baddeley and Della Sala, 1996) and is necessary for the performance of
tasks requiring the planning and selection of new and appropriate
response strategies (Shallice and Burgess, 1993; Robbins, 1996).
Patients with PFC damage perform poorly on tasks such as the Tower of
London task that depend on planning a sequence of responses (Shallice,
1982; Owen et al., 1990; Robbins, 1996). In normal subjects, PFC
activation is observed during performance of the Tower of London task
(Baker et al., 1996) as well as during tasks requiring the generation
of novel response sequences (Jueptner et al., 1996). Thus, both the
short-term retention of visuo-spatial information and the central
executive components of working memory have been linked to the PFC.
The delayed task used in the present study does not require the active
retention of information within the PFC because lidocaine-induced inactivation of the PFC before or during the delay period does not
disrupt performance (Seamans et al., 1995). Likewise, lidocaine-induced inactivations of the PFC do not affect performance of the
nondelayed task even though this task requires the short-term retention
of spatial information. It has been postulated that imposing a delay in
a radial-arm maze task biases rats to forage prospectively, whereas
nondelayed tasks bias rats to forage retrospectively (Cook et al.,
1985; Floresco et al., 1997). On the delayed task, foraging is severely
disrupted after transient lidocaine inactivations of the PFC at a time
when previously acquired information must be accessed and integrated
into a prospective foraging strategy (Seamans et al., 1995). These
data, therefore, are consistent with a role of the rat PFC in executive
functions related to planning.
In the rat, the short-term retention of spatial information may be
mediated by the hippocampal formation and overlying cortices. Rats with
lesions of the hippocampus are impaired in memory for spatial location
(Morris et al., 1991; Jarrard, 1993), whereas transient lesions of the
ventral hippocampus, similar to those reported here, are effective in
disrupting the short-term acquisition and retention of spatial
information (Poucet et al., 1991; Floreso et al., 1996, 1997). The
importance of the hippocampal afferents in the present study was likely
attributable to this task being spatially cued and, therefore, biased
the use of circuits involving the hippocampal formation. D1
receptors conceivably could modulate functional inputs from other brain
regions, depending on the nature of the task. Asymetric
"disconnections" of the ventral hippocampus and PFC selectively
disrupt the delayed-working-memory task (Floresco et al., 1997),
possibly by disconnecting the spatial memory buffer in the temporal
lobe from the central executive in the PFC. The present results
indicated that D1 receptors in the PFC may modulate the
transfer of spatial information from the hippocampus to the PFC at a
time when a prospective series of response must be organized and
executed.
Potential mechanisms for D1 receptor modulation of
PFC function
Insight into the mechanisms by which D1 receptor
activation modulates both the active retention of information in the
PFC and the processing of information accessed from a spatial memory buffer in the temporal lobe is provided by recent electrophysiological studies. It is important to note that the effect of DA within the PFC
is determined by the activity level of PFC neurons and the specific
inputs that are driving this activity. Although DA inhibits spontaneous
activity within the PFC of the anethesized rat (Ferron et al., 1984;
Mantz et al., 1988; Pirot et al., 1992), it enhances task-related
single-unit activity more than background activity in the behaving
primate (Sawaguchi et al., 1988, 1990a). DA (but not VTA stimulation)
also enhances responses evoked by hippocampal stimulation in the
anesthetized rat and use-dependent changes in synaptic efficacy in the
hippocampal-PFC pathway that may be associated with learning
(Dòyere et al., 1993; Jay et al., 1995, 1996). Thus, DA may
enhance task- or learning-related activity relative to spontaneous or
background activity within the PFC.
In vitro studies suggest that DA influences the behavior of
PFC neurons in a way that is consistent with this hypothesis. DA
directly depolarizes interneurons in the PFC and enhances spontaneous and evoked IPSPs recorded in pyramidal neurons (Penit-Soria et al.,
1987; Yang et al., 1997; Zheng et al., 1997). Accordingly, the
suppressive action of DA on spontaneous firing of PFC neurons in
vivo is blocked by previous application of a GABA antagonist (Pirot et al., 1992), suggesting that DA acts through interneurons in
the PFC to reduce spontaneous activity of pyramidal neurons. In
contrast, the effects of strong depolarizing inputs that bring the
neuron to spike threshold are enhanced directly by DA via the
D1 receptor (Yang and Seamans, 1996). In this way, DA
acting through the D1 receptor may enhance selectively the
effects of the most salient inputs to PFC neurons relative to
background or spontaneous inputs. Supranormal stimulation of the DA
system in the PFC may strongly activate inhibitory mechanisms so as to severely restrict the number of inputs that potentially could evoke
firing of PFC neurons. Response perseveration may be one consequence of
restricting afferent input in this manner. In fact, Zahrt et al. (1997)
reported recently that D1 receptor agonists microinjected
into the PFC of rats did impair delayed responding by increasing
response perservation.
If D1 receptors act as a gating mechanism to control the
responses of layer V PFC output neurons, in the manner described above,
it follows that D1 antagonists would attenuate functional signals in afferent pathways including the hippocampal-PFC projection relative to spontaneous firing in PFC output neurons. Indeed, Sawaguchi
(1997) has demonstrated recently that iontophoresis of SCH-23390 into
the premotor cortex of primates decreased delay-period activity
significantly more than background activity during a delayed-response
task. In the present delayed-foraging task, blockade of D1
receptors would be predicted to decrease the effectiveness of
functional inputs from the hippocampus relative to spontaneous activity, possibly resulting in random modes of behavior. This was the
pattern of results observed here after bilateral injections of
SCH-23390 into the PL, or unilateral D1 receptor blockade
in the PL, in combination with a transient lesion of the contralateral vSub.
Conclusions
D1 receptors appear to play an important role in at
least two different aspects of working memory function in the PFC: (1) the ability to hold information in an active state for a short time, as
shown previously (Sawaguchi and Goldman-Rakic, 1994; Williams and
Goldman-Rakic, 1995), and (2) the recall of information from a spatial
memory buffer via a hippocampal-PFC circuit and the integration of
spatial memory into a prospective response strategy. The recall of
spatial information from a buffer in the hippocampal formation may
involve "top-down" feedback inputs from the PFC to the temporal
cortex in a manner analogous to that proposed by Desimone and
colleagues (Desimone et al., 1994; Miller et al., 1996) for visual
recognition memory but over much greater temporal intervals. Our
research is consistent with a neural model in which the executive
system and the spatial memory buffer are located in separate regions of
the rat cortex, namely the PFC and temporal lobe, respectively, and
that DA modulates the flow of information between these two regions via
the D1 receptor.
| |
FOOTNOTES |
Received Aug. 29, 1997; revised Dec. 3, 1997; accepted Dec. 4, 1997.
This research was supported by a grant from the Natural Sciences and
Engineering Research Council of Canada to A.G.P. S.B.F. is the
recipient of a Natural Sciences and Engineering Research Council
scholarship, and J.K.S. holds a University of British Coloumbia
Graduate Fellowship. We thank Glen Wundelich and Tony Drew for their
assistance with behavioral testing.
Correspondence should be addressed to Anthony G. Phillips, Department
of Psychology, University of British Columbia, 2136 West Mall,
Vancouver, British Columbia, Canada V6T 1Z4.
| |
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Top
Abstract
Introduction
