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The Journal of Neuroscience, January 1, 2000, 20(1):485-494
Destruction and Creation of Spatial Tuning by Disinhibition:
GABAA Blockade of Prefrontal Cortical Neurons Engaged
by Working Memory
Srinivas G.
Rao,
Graham V.
Williams, and
Patricia S.
Goldman-Rakic
Section of Neurobiology, Yale University School of Medicine, New
Haven, Connecticut 06510
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ABSTRACT |
Local circuit neurons in the dorsolateral prefrontal cortex (dPFC)
of monkeys have been implicated in the cellular basis of working
memory. To further elucidate the role of inhibition in spatial tuning,
we iontophoresed bicuculline methiodide (BMI) onto functionally
characterized neurons in the dPFC of monkeys performing an oculomotor
delayed response task. This GABAA blockade revealed that
both putative interneurons and pyramidal cells possess significant
inhibitory tone in the awake, behaving monkey. In addition, BMI
application primarily resulted in the loss of previously extant spatial
tuning in both cell types through reduction of both isodirectional and
cross-directional inhibition. This tuning loss occurred in both the
sensorimotor and mnemonic phases of the task, although the delay
activity of prefrontal neurons appeared to be particularly affected.
Finally, application of BMI also created significant spatial tuning in
a sizable minority of units that were untuned in the control condition.
Visual field analysis of such tuning suggests that it is likely caused
by the unmasking of normally suppressed spatially tuned excitatory
input. These findings provide the first direct evidence of directional
inhibitory modulation of pyramidal cell and interneuron firing in both
the mnemonic and sensorimotor phases of the working memory process, and
they implicate a further role for GABAergic interneurons in the
construction of spatial tuning in prefrontal cortex.
Key words:
primate; inhibition; prefrontal cortex; interneurons; spatial tuning; bicuculline; working memory; fast spiking
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INTRODUCTION |
The role of excitatory and
inhibitory elements in the construction of spatially selective activity
has been studied pharmacologically at the single-unit level in several
sensory cortical areas. In the primary visual cortex (V1), both
broadening of orientation tuning (Sillito, 1984 ; Sato et al., 1996) and
reduction of directional selectivity (Murthy and Humphrey, 1999) have
been observed with the application of bicuculline methiodide (BMI), a
GABAA receptor antagonist. Microiontophoresis of
GABA has been shown to reduce orientation selectivity of the response
of cells recorded ~500 µm away (Eysel et al., 1990). In primary
somatosensory cortex, application of BMI was found to result in an
increase of the size of receptive fields (Alloway et al., 1989; Alloway
and Burton, 1991). Finally, in the rat barrel cortex, application of
BMI and GABA resulted in reduced and increased spatial selectivity,
respectively, of both putative GABAergic and spiny stellate neurons
(Kyriazi et al., 1996). Overall, these results suggest that
GABAA-mediated inhibition plays an important role
in the generation of spatial selectivity in the primary sensory areas
of cortex.
Spatially selective activity in the dorsolateral prefrontal cortex
(dPFC) takes the form of the directionally selective neuronal responses
during the mnemonic and sensorimotor periods of an oculomotor delayed
response (ODR) task, a test of spatial working memory (Funahashi et
al., 1989, 1990, 1991; Chafee and Goldman-Rakic, 1998; Rao et al.,
1999). Such directionally selective mnemonic activity is thought to
represent the neural substrate of spatial working memory (Funahashi et
al., 1989). However, little is known about the precise role of
inhibitory mechanisms in the regulation of such activity, although
several studies have suggested that inhibition is important to working
memory function. Injection of bicuculline into the dPFC of monkeys has
been shown to disrupt the performance of a delayed response task
(Sawaguchi et al., 1988, 1989). Two studies using single-unit recording
in the dPFC of awake, behaving monkeys have demonstrated the
relationships of spatial tuning between putative pyramidal cells (RS)
and interneurons (FS). Wilson et al. (1994) demonstrated
inverted patterns of activity between nearby (i.e., <400 µm) FS and
RS units while monkeys engaged in various spatial, sensory-guided
tasks, leading to the hypothesis that cross-directional inhibition may
be important for spatial tuning in the monkey dPFC (Goldman-Rakic,
1995b). In a recent paper (Rao et al., 1999), we examined the tuning
patterns of simultaneously recorded FS-RS pairs of monkeys performing
the same eight-target ODR task considered in this paper. Members
of such pairs were found to exhibit tuning properties that were very
similar to each other, providing evidence that isodirectional
inhibition between closely adjacent units may play an important role in
spatial tuning of cortical neurons.
To elucidate the role of inhibition in the cellular circuits underlying
spatial working memory, we microiontophoretically applied BMI onto
functionally characterized prefrontal neurons in monkeys performing an
ODR task. By pharmacologically disconnecting a significant fraction of
the GABAA-mediated inhibitory input, we were able
to determine the degree to which a neuron's spatial tuning is
dependent on such input. This enabled us to characterize further the
directional nature of the inhibition in the prefrontal cortex.
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MATERIALS AND METHODS |
Experimental methods. Extracellular recordings were
made in the left dPFC of two rhesus monkeys (Macaca mulata),
in accordance with the Yale University Animal Care and Use Committee,
as recently detailed in Rao et al. (1999). The animals were trained in
the spatial ODR task shown in Figure 1.
The monkey commenced each trial of the task by fixating within 2° of
a central stimulus for 0.5 sec. The monkey then continued to fixate
while one of eight peripheral stimuli (45° separation in
circumference, 13° eccentricity) was illuminated for 0.5 sec. This
was followed by a delay period of 2.5 or 3.0 sec, during which the
monkey maintained fixation. At the end of this time, the central
stimulus was extinguished, and the monkey had to make a saccade to
within both 0.5 sec and 2° of the position of the
previously shown peripheral stimulus to be rewarded with fruit juice.
The peripheral cues were presented in a semi-random order across trials
such that, during the delay period, the monkey had to remember the cue
position shown within the present trial to make the correct response.
The monkey's eye position was monitored using a scleral
implant/field-coil system (CNC-Engineering, Seattle, WA), and the ODR
task was generated by a TEMPO system (Reflective Computing, St. Louis,
MO).
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Figure 1.
The eight-target oculomotor delayed-response (ODR)
task. Schematic of the ODR task showing the temporal relationship of
the Cue, Delay, Pre, and Post epochs. Note that the latter two
represent the presaccadic and postsaccadic components, respectively, of
the response phase of the task. A 2.5 sec delay is shown, although both
2.5 and 3.0 sec delays were used. Inset, Cue locations
for the eight-target ODR task. All cues were located at a 13°
eccentricity.
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The dura was punctured using a 25-gauge guide tube, and the electrode
was advanced into the brain using a Narishige (Tokyo, Japan)
MD-2 digital microdrive. The iontophoretic electrode itself was
fabricated from seven-barrel glass (Friedrich and Dimmock, Millville,
NJ) and 20 or 33 µm carbon fiber (ESLI, San Diego, CA) on a custom
electrode puller. Two of the barrels of the microelectrode were filled
with BMI at 1-2 mM concentrations, pH 4.0, and a
NeuroPhore BH-2 iontophoretic system from Medical Systems Corporation
(Greenvale, NY) was used to control drug delivery. The remaining two
pairs of barrels on the microelectrode were filled with other drugs (generally dopaminergic or serotonergic agents) that varied on a
monthly basis (Williams et al., 1997, 1998a,b). The drugs remained in
the drug barrels for no more than 4 hr and remained protected from
light during this time. The stability of BMI, in particular, was
assured even toward the end of the experiment because its iontophoresis
always resulted in increased unit activity. BMI was ejected at currents
that typically varied from 15 to 25 nA (total range 10-250 nA), and a
cyclical retaining current was used with currents ranging from 2 to 5 nA. The ejection current was typically started low and carefully
titrated upward toward a stable value that resulted in a noticable
increase in activity in the units being recorded from. Such careful
titration was necessary to avoid localized epileptiform (bursting)
activity, which manifested as rhythmic, large amplitude, polymorphic
waveforms associated with a distinctive sound on the audio monitor.
Epileptiform activity developed in <5% of the experiments performed,
and in all such cases, recording was abandoned.
At each recording depth, we generally tested 8-12 trials of the task
at each of the eight cue locations in a drug-free control condition.
Upon establishing the stability of the units' waveforms and activity
at the site, this control condition was followed by a similar number of
trials during drug administration. These conditions were typically
followed by both post-drug and recovery conditions, with the former
representing a "wash out" period for the drug. This
pattern control, drug, post-drug, and recoverywas repeated up to
three times at a given site. Initially, we determined that neurons
generally recovered very poorly to bicuculline administration, presumably because of the long half-life of the drug. Hence, BMI was
usually the sole drug tested at a site. Moreover, in those situations
when multiple drugs were tested at one site, BMI was always tested last.
Neuronal data were acquired by a micro1401/Spike2 system (Cambridge
Electronic Design, Cambridge, UK), which can sort up to eight units at
a single site (we have successfully isolated as many as five) based on
a waveform-matching algorithm. Units were categorized as being FS
primarily on the basis of their short spike-base width (<0.90 msec),
characteristic sound, relatively low amplitude, and relatively high
firing rates (Rao et al., 1999). Finally, although some RS neurons
could be tracked for several hundred micrometers, FS cells were rarely
tracked for >20 µm, presumably reflecting the large principal apical
dendrites of the former and the smaller soma size and dendritic field
of the latter.
Analysis. For purposes of tuning analysis, each trial in the
ODR was divided into four epochsCue, Delay, Pre, and Postand the
average spike rate across each epoch within a single trial was used in
subsequent analysis (Fig. 1). The Cue epoch lasts for 0.5 sec and
corresponds to the stimulus presentation phase of the task. Delay lasts
for 2.5 or 3.0 sec and reflects the mnemonic component of the task. The
presaccadic response epoch, Pre, starts immediately after the Delay
epoch and lasts 0.25 sec. As the name implies, the bulk of the neuronal
activity during the Pre epoch is associated with saccade initiation
(Funahashi et al., 1989). By definition, a successful saccade is
completed by the time the postsaccadic epoch, Post, begins: 0.5 sec
after the end of Delay and lasting for 0.5 sec. The animal receives its
reward 0.50-0.55 sec after Delay at the onset of the Post epoch. A
given unit can show spatial tuning in none, any, or all of these epochs
(Funahashi et al., 1989, 1990, 1991; Rao et al., 1999).
The directionality of a unit's response in each of the four epochs was
assessed statistically using a vector algorithm technique that provides
a value for the overall strength and direction of tuning as detailed in
Rao et al. (1999). An important step of this algorithm is the
computation of the overall vector of a unit's firing within a
condition. The magnitude of such a vector can result either from bursts
of firing in a few trials in the untuned case or from a pattern of
repeatable, spatially specific activity that is maintained throughout
the majority of trials within the condition, a pattern that corresponds
to our definition of spatial tuning. To discriminate between these
tuned and untuned cases, we first calculate n individual
"loop" vectors, each derived from the firing rates at the eight
target directions for the nth trial. We then assess the
contribution (using the scalar product) that the individual loop
vectors made to the overall vector. The values of these scalar products
vary between  1 and 1 (because of normalization). In the untuned case,
the scalar products will tend to cluster around zero. However, as a
unit's firing becomes more directional, the values of these scalar
products will increase, equaling 1 in the ideal case in which a neuron
only fires for targets located at one direction. Hence to statistically
assess tuning, the scalar products are compared with thresholds using a
nonparametric test (Wilcoxon signed-rank test, p < 0.05). The most basic level of tuning for our purposes corresponds to
the case in which most of the loop vectors are within 90°
of the overall vector. In this situation, the values of the dot
products will be statistically greater than a threshold of 0. If the
unit fails this test, it is declared untuned and assigned a tuning
factor (TF) of zero. However, if the scalar product values are
statistically greater than zero, the values are then compared with
increasing thresholds at 0.05 increments up to a value of 0.5, providing TFs ranging from 1 to 10. Obviously, increasing values of the
TF correspond to increasingly significant spatial tuning.
The direction of tuning of a unit is indicated by the algorithm as a
tuning angle,  , that varies between 0 and 360° and is calculated
by computing the median angle of the individual loop vectors. [This
choice of estimators for the overall direction of a unit's response
was directed by the "sturdiness" against outliers that the circular
median estimator possesses (Fisher, 1993). Conversely, outliers can
have a profound effect on the angle of the overall vector, an otherwise
natural choice as an estimator for this parameter.] Because of the
vector nature of the analysis, the tuning angle generally does not
necessarily coincide exactly with any of the eight target locations.
The index (target location) closest to the overall tuning angle of a
given neuron was defined as that unit's "preferred" index. The
preferred index and the two indices immediately adjacent were defined
as being the "isodirectional" indices. The three indices 180°
distant to the three isodirectional indices were defined as the
"cross-directional" indices.
The two particular changes in tuning occurring between the control and
bicuculline conditions that were of interest to us were the creation
and loss of statistically significant spatial tuning. We defined an
increase in TF from a value of zero in the control condition to a value
of 1 or more in the bicuculline condition as corresponding to the
creation of tuning. Conversely, a decrease in TF from a value of 1 or
more in the control to zero in the drug condition signified destruction
or loss of tuning. In those units in which tuning in a given epoch in
the control was destroyed by BMI application, the tuning angle,
isodirectional indices, and cross-directional indices were all
determined in the control condition. However, in the case of
application of BMI creating a unit's tuning in a given epoch, these
parameters had to be calculated in the drug condition.
The vector algorithm was implemented as a c++ program, which
takes as input intermediate files created by a Spike2 script and
creates an output file that is then imported directly into a database
created in Filemaker from Claris (Santa Clara, CA). Other analyses and
graphs were generated using Statview (Abacus Concepts, Berkeley, CA)
and Deltagraph (DeltaPoint, Monterey, CA), respectively.
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RESULTS |
A total of 86 neurons were tested iontophoretically with BMI. Of
these, 66 units were classified as RS units and 20 were classified as
FS neurons. The application of BMI resulted in a statistically significant increase in overall activity in ~70% of FS and RS neurons tested, as assessed by comparing the average spike rates across
the trials of the control and BMI conditions using a one-way factorial
ANOVA (p < 0.05). The magnitude of such
activity increases varied widely, from ~20% to more than fivefold,
and no apparent differences between the FS and RS cells were noted. An
example of an FS-RS pair (recorded simultaneously at the same site)
onto which BMI was iontophoresed is shown in Figure
2A. Note the
severalfold increase in the mean firing rate of both neurons with the
application of bicuculline. In four RS neurons, we observed a
paradoxical reduction in activity with BMI administration; this may
have been caused by aberrant waveform morphology or depolarization
block during BMI administration. In all such cases, any previously
extant spatial tuning was lost.
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Figure 2.
Effects of BMI application on activity and tuning
of PFC neurons. A, An example of an FS-RS pair
(recorded simultaneously at the same site) onto which BMI was
iontophoresed at 20 nA. The vertical axis represents
firing rate in Hertz, and the horizontal axis is time; a
time bar denoting 100 sec is indicated for scale. Note
the severalfold increase in the mean firing rate of both neurons with
the application of BMI. B, The results of the
iontophoretic application of BMI on spatial tuning for the entire
neuronal population (i.e., combined FS and RS populations). The
n values in the top and
bottom halves of the figure represent the number of
units that were untuned or tuned, respectively, in each epoch in the
control condition. The bar graphs represent the
percentage of this number that developed (top) or lost
(bottom) tuning with the application of BMI.
Top, Application of BMI created spatial tuning in a
considerable number of neurons that were untuned in the control
condition, and the frequency of this phenomenon increased as the trial
progressed from the Cue epoch to the Post
epoch. Bottom, The predominant effect on previously
extant tuning was the loss of this tuning; Delay
appeared most susceptible to this effect.
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BMI application onto tuned neurons
In the control condition, ~70% of RS and FS neurons that were
subsequently tested with bicuculline exhibited statistically significant spatial tuning (i.e., TF  1) in at least one of the four
epochs. The results of the iontophoretic application of BMI on spatial
tuning for the entire neuronal population (i.e., combined FS and RS
populations) are shown in Figure 2B. The n
values in the top and bottom halves of the figure represent the number
of units that were untuned or tuned, respectively, in each epoch in the
control condition. The bar graphs themselves represent the percentage
of this number in which tuning was created (top) or lost
(bottom) with the application of BMI. From the bottom half
of the figure, we can see that the predominant effect of BMI
application on RS and FS neurons that were spatially tuned in the
control condition was the loss of this tuning. Some variation was noted
between epochs, with Delay period activity being the most susceptible
to tuning destruction by the loss of
GABAA-mediated inhibition, and Cue period
activity being the least vulnerable. An example of an FS neuron that
lost its Delay tuning with the application of BMI at 15 nA is shown in
Figure 3 in rastergram and histogram
format for the preferred index and a cross-directional index
(A) and in polar-plot format for all directions
(B). In the control condition, this unit displayed a
highly statistically significant tuned response (TF = 6, = 32°) with a preferred index of 45°. From Figure
3A,B, it is evident that in the
control condition, activation during Delay was present for targets
located at 0 and 45°, whereas suppression of activity occurred at the cross-directional indices (i.e., those located at 180, 225, and 270°). Application of BMI at 15 nA resulted in the destruction of
tuning (TF = 0 in this condition), primarily as a result of increased activity at the cross-directional indices. In Figure 3A, it is apparent that although activity at the 45° index
was modestly increased with the application of BMI, activity at the 225° target location showed marked elevation. In Figure
3B, statistically significant increases (Student's unpaired
t test; p < 0.05) in activity occurred at
all directions, with the exceptions of the isodirectional indices
(i.e., 0, 45, 90°).
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Figure 3.
Loss of Delay tuning in an FS neuron with BMI
application. A, Rastergrams and histograms (bin width 50 msec) presented for the preferred index (45°) and a cross-directional
index (225°) for an FS neuron. In the control condition
(left), this unit shows marked activation during
Delay at the 45° index. However, the unit's response
is relatively suppressed at the 225° location. With the application
of BMI at 15 nA (right), Cue activity at
both indices equalizes, and the unit's tuning in this epoch is lost.
B, The data for the same unit as above presented in
polar plot form. Means and standard error measurements for all eight
indices are presented for both the Control and
BMI conditions. Statistically significant differences in
activity (two-tailed Student's t test,
p < 0.05) between the two conditions at each index
are denoted with asterisks. In the control condition,
the unit shows strong tuning (TF=6, =
32°) with preferential activation at the
isodirectional indices (45, 0, and to a lesser degree 90°) and
suppression at the cross-directional indices (180, 225, and 270°).
With the application of BMI, activity at the isodirectional indices is
not significantly increased. However, the activity at the
cross-directional indices is markedly enhanced, reaching significance
at three indices.
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An example of an RS neuron that lost its Cue tuning with the
application of BMI at 15 nA is shown in Figure
4, again in both rastergram and histogram
format (A) and polar plot format
(B). This unit showed significant Cue tuning during
the control condition (TF = 4, = 99°). Activation was
primarily present for targets located at 90° (the preferred index)
and 135°, whereas suppression was noted at the cross-directional
indices (225, 270, and 315°). Application of BMI at 15 nA resulted in
the destruction of this tuning once again as a result of increased
activity in the cross-directional indices. In Figure
4A, it is apparent that the activity for the cross-directional target location (225°) was markedly elevated over
the control condition with the application of BMI, whereas activity at
the preferred direction was relatively unchanged. In Figure
4B, we see that statistically significant increases (Student's unpaired t test; p < 0.05) in
activity occurred for targets located at 0, 225, and 315°.
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Figure 4.
Loss of Cue tuning in an RS
neuron with BMI application. A, Rastergrams and
histograms (bin width 50 msec) presented for the preferred index
(90°) and a cross-directional index (225°) for an RS neuron. In the
control condition (left), this unit shows strong
activation in the Cue epoch at the 90 and 135°
indices. However, the unit's response is relatively suppressed at the
225° location. With the application of BMI at 15 nA
(right), Cue activity at both indices
becomes equal, resulting in tuning loss. B, The data for
the same unit as above presented in polar plot form. Means and standard
error measurements for all eight indices are presented for both the
control and BMI conditions. Statistically significant differences in
activity (two-tailed Student's t test,
p < 0.05) between the two conditions at each index
are denoted with asterisks. In the control condition,
the unit shows strong Cue tuning (TF=4,
=99°) with strong activation at the isodirectional
indices (90, 135, and to a lesser degree 45°) and suppression at the
cross-directional indices (225, 270, and 315°). With the application
of BMI, activity at the isodirectional indices is relatively unchanged.
However, the activity at the cross-directional indices is markedly
enhanced, reaching significance at both 225 and 315°.
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An example of an FS neuron that loses its tuning in the postsaccadic
epoch is shown in Figures 5A
in polar plot format. In the control condition, the unit shows broad
excitation for targets in the ipsilateral visual field with very little
activation for targets in the contralateral visual field (TF = 1, = 177°, preferred index at 180°). However, application of
BMI at 20 nA causes a statistically significant
(p < 0.05) increase in activity at all target
locations except 90°, resulting in a complete loss of spatial selectivity.
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Figure 5.
Tuning loss during Post and creation of Pre tuning
in two different FS units with BMI application. A, Loss
of Post tuning in an FS neuron with the application of
BMI. In the control condition, this unit shows broad activation for all
targets located in the ipsilateral visual field (TF=1,
=186°, preferred index = 180°). Application
of BMI at 20 nA results in the complete loss of spatial selectivity in
this unit's Post response. B, The effects of BMI
application onto an untuned FS unit. In the control condition, this
unit displayed very little spatial selectivity during the
Pre epoch. Application of BMI resulted in a significant
increase in activity at only one cue location, 90°, the preferred
direction of firing for this unit.
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BMI application onto untuned neurons
Application of BMI created spatial tuning in a considerable number
of neurons that were untuned in the control condition (Fig. 2B, top). The frequency of this phenomenon
increased as the trial progressed from the Cue to the Post epochs, with
the latter displaying more than twice the percentage of tuning creation
of the former. The effect of BMI application onto an untuned FS unit is
shown in Figure 5B. In the control condition, this unit
displayed very little spatial selectivity during the Pre epoch.
Application of BMI resulted in a significant increase in activity at
only one cue location, 90°, the preferred direction of firing for
this unit in the drug condition.
In Figure 6 is shown an RS unit in which
statistically significant Cue and Post tuning was created by BMI
application. It is evident from Figures 6A
(left),B, that this unit's activity in both of
these epochs in the control condition was relatively slow and lacked
spatial selectivity (TF = 0 for both epochs). However, application
of BMI at 15 nA resulted in a spatially selective increase in activity
during both of these epochs (Fig. 6A, right, B). Activity in
Cue increased markedly for targets located at and around 0° with the
application of BMI; however, activity for cues located in the
ipsilateral visual field (135, 180, and 225°) was only minimally
increased over the control condition. This pattern of activity increase
resulted in a statistically significant tuning in this epoch in the BMI
condition (TF = 2, =16°). In contrast, activity during Post
increased primarily in the ipsilateral visual field with the
application of BMI, again resulting in statistically significant tuning
(TF = 1, = 211°, preferred index of 225°). Note the
near inversion of tuning angles between the Cue and Post epochs in this
unit. Such inversion is not an uncommon pattern of activation in the
prefrontal cortex (Funahashi et al., 1989, 1991; Rao et al., 1999).
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Figure 6.
Creation of both Cue and Post tuning in
an RS neuron with the application of BMI. A, Rastergram
and histogram (bin width 50 msec) data presented for both the 0 and
225° directions for this RS neuron. In the control condition
(left), this unit's activity in both the
Cue and Post epochs was relatively slow
and lacked spatial selectivity (TF = 0 for both epochs). However,
application of BMI at 15 nA resulted in a spatially selective increase
in activity during both of these epochs (right).
Activity in Cue increased markedly at 0° (contralateral visual field)
with the application of BMI; however, activity for cues located at
225° was only minimally increased over the control condition. In
contrast, activity during Post increased preferentially at 225°
(ipsilateral visual field) with the application of BMI.
B, The data for the same unit as above presented in
polar plot form. Means and standard error measurements for all eight
indices are presented for both control and BMI conditions.
Statistically significant differences in activity (two-tailed
Student's t test, p < 0.05)
between the two conditions at each index are denoted with
asterisks. In the control condition, the unit shows
suppressed, nonspatially specific activity during both the
Cue (left) and Post
(right) epochs (TF = 0 in both cases). However,
application of BMI resulted in preferential activation of this unit
during Cue at and around the 0° index, thus resulting in
statistically significant tuning (TF=2,
=18°). Conversely, activity increases during
Post during the drug condition occurred primarily around the 225°
location, resulting in a TF = 1 and a = 211°.
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Population analyses
The mechanisms by which changes in tuning occurred with the
application of BMI were examined at the population level to ascertain whether these changes show directional dependence. In particular, we
examined the occurrence of isodirectional or cross-directional disinhibition for both destruction and creation of tuning. We first
determined the percentage of units within a given population displaying
statistically significant increases in activity
(p < 0.05, unpaired Student's t
test, control vs BMI conditions) at the indices located in the
isodirectional and cross-directional indices. (Because there were three
indices each within the isodirectional and cross-directional fields, a
statistically significant change in activity at an individual index was
counted as one-third for a given unit. Hence, a unit that showed
significant increases in activity at all three cross-directional
indices, for example, would count as one toward the total.) For the RS
neurons, this analysis was performed on both an epoch-by-epoch basis
and at the level of the entire population. For the FS neurons, however, only a population level analysis could be performed because of the
relatively limited numbers of such neurons. The results are shown in
Figure 7A. For both the RS and
FS populations (Fig. 7A, right), there was a bias
toward cross-directional disinhibition in units whose tuning was
destroyed with BMI. On the other hand, a bias toward isodirectional
disinhibition was present in units of both populations that developed
tuning with the application of BMI. This general pattern was also
apparent for the Cue, Delay, and Post epochs for RS neurons (Fig.
7A, left). During the Delay epoch, a large
percentage of units whose tuning was affected by BMI application showed
statistically significant changes in activity in the isodirectional and
cross-directional indices. Finally, we found no neurons that had
lost tuning solely through isodirectional disinhibition.
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Figure 7.
Isodirectional and cross-directional disinhibition
in FS and RS populations. A, The percentage of units
displaying statistically significant increases in activity
(p < 0.05, unpaired Student's
t test, control vs BMI conditions) at the indices
located in the isodirectional (top) and
cross-directional (bottom) target locations for RS units
by epoch (left) and for the RS and FS populations
(right). As defined, there are three indices each within
the isodirectional and cross-directional fields; hence, a statistically
significant change in activity at an individual index is counted as
one-third for a given unit. Within each epoch (left) or
population (right), data for tuning destruction and
creation are presented in the bar graphs on the
left and right, respectively. The
n values within each bar refer to the total number of
units from which the proportions that the bar graphs represent were
calculated. Left, In all epochs, there was a bias toward
cross-directional disinhibition in units whose tuning was destroyed by
BMI application, and a bias toward isodirectional disinhibition in
units whose tuning was created by BMI application. Note that during
Delay, a relatively large percentage of units whose tuning was affected
by BMI application showed statistically significant changes in activity
in the isodirectional and cross-directional directions.
Right, For both the RS and FS populations, there was an overall bias toward
cross-directional disinhibition in units whose tuning was destroyed
with BMI and a bias toward isodirectional disinhibition in units that
developed tuning with the application of BMI. B,
Preferred index centered mean relative change plots for the RS units in
Delay. The preferred index (normalized at 0°) is indicated, and all
other indices are shown relative to this index. The
ordinate shows the percentage increase of the population
at each index. The error bars denote the SEM (see Results for further
details). Top, Tuning destruction. Activity increases in
the isodirections were similar to those seen in the cross-directions. A
factorial ANOVA comparing the combined data at all three isodirectional
indices with the combined data at all three cross-directional indices
was not significant. These results suggest that isodirectional and
cross-directional disinhibition contributed relatively evenly to the
loss of tuning in this population. Bottom, Tuning
creation. A significant increase in activity at the combined
isodirectional indices was found by ANOVA in this case
(p = 0.019), suggesting that disinhibition
at the isodirectional indices was more important than that occurring at
the cross-directions for creation of tuning.
|
|
We further assessed the magnitude of activation at the isodirectional
and cross-directional indices using a "mean- relative change plot"
that was centered on the preferred index. This analysis was effected by
first determining the relative change in activity at each index in the
BMI condition as compared with the mean of the activity at all indices
in the control condition for each unit. These values were then
centered, in the current analysis, on the preferred direction for each
unit. Finally, the mean and standard errors of the activity changes for
each direction relative to the preferred direction were calculated
across all units in a given population. The results for RS neurons in
the delay epoch are shown in Figures 7B for tuning
destruction (top) and creation (bottom). For the
former, activity increases at all of the indices were relatively even.
Not surprisingly, activity increases in the isodirections were not
statistically different from those at the cross-directional indices.
These results suggest that isodirectional and cross-directional
disinhibition contributed relatively evenly to the tuning loss in this
population. However, for those neurons whose tuning was created with
BMI, a significant increase in activity at the isodirectional indices
was found, confirming the results of Figure 7A
(left). Note that the large variances found in the data
presented in Figure 7B (top) and
(bottom) were primarily a result of the wide range of
activity increases that occurred with BMI application.
To help ascertain the etiology of tuning creation (i.e., whether this
phenomenon resulted from the release of suppressed excitatory input or
from more nonspecific disinhibition), we analyzed the visual field
preference of tuning that was created in the RS neuronal population.
These results are shown in Figure
8A. The spatial tuning
that became evident with the application of BMI showed a contralateral
visual field bias during the Cue and Delay epochs (>55%). The Pre
epoch was relatively unbiased. Finally, a strong ipsilateral visual
bias was noted during the Post epoch (almost 75% ipsilateral vs
~25% contralateral). These data are confirmed for the Delay and Post
epochs (the epochs showing the most visual field bias) in the mean
relative change plots centered on the 270° location in Figure
8B (top) and (bottom),
respectively. In Delay, activity increases at the contralateral
locations were greater (although not statistically significantly) than
those in the ipsilateral visual field. These results were in contrast to those obtained in Post, where increases in the ipsilateral indices
were profoundly larger than those noted in the contralateral indices.
However, these changes did not reach statistical significance. (The
high variance present in this data were caused, again, by the wide
variability in activity increases that occurred with BMI application.
However, in these analyses, variability was further increased because
of the fact that data in these graphs were centered about the 270°
target location instead of the preferred direction for a given cell. At
a population level, this resulted in the combining of the
isodirectional data of one unit with the cross-directional data of
another, data that were shown to have significantly different means in
Fig. 7B.)
View larger version (30K):
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|
Figure 8.
Visual field preference of tuning that was created
in the RS neuronal population. A, Percentage of the
total number of units (shown by n) that became tuned in
each epoch that demonstrated ipsilateral or contralateral visual field
tuning. The spatial tuning that became evident with the application of
BMI showed a contralateral visual field bias during the
Cue (>55%) and Delay (>75%) epochs.
The Pre epoch was relatively unbiased. Finally, a strong
ipsilateral visual bias was noted during the Post epoch
(almost 75% ipsilateral vs ~25% contralateral). B,
Visual field centered mean relative change plots for
Delay and Post data. The ordinate shows
the percentage increase in activity of the population at each indicated
target location, and the error bars denote the SEM (see Results for
further details). Top, During Delay, this
analysis reveals some increased disinhibition for indices located in
the contralateral visual field (i.e., 315, 0, and 225°). No
significant differences were found between these data by ANOVA.
Bottom, In Post, increases in the
ipsilateral indices (135, 180, 225°) were profoundly larger than
those noted in the contralateral indices. Again, these changes did not
reach statistical significance by ANOVA.
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|
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DISCUSSION |
In the current work, we investigated the action of
GABAA-mediated inhibition on single units in the
primate dPFC involved in the eight-target ODR task. We found that both
the FS and RS neurons receive significant GABAergic tone in
vivo. The predominant effect of BMI application on spatially tuned
FS and RS neurons was found to be tuning loss, mediated by a
combination of isodirectional and cross-directional disinhibition.
Mnemonic activity appeared somewhat more susceptible to tuning loss
than did other epochs. Finally, we found that a subpopulation of
previously untuned neurons became tuned with the application of BMI.
The tuning thus created showed a contralateral visual field bias in Cue
and became progressively more ipsilaterally biased as the task progressed.
Effects of BMI on overall activity
BMI application produced a general increase in the overall
activity level of both FS and RS neurons. This result was anticipated for the RS population given the evidence on the connectivity between inhibitory interneurons and pyramidal neurons in prefrontal cortex (Williams et al., 1992; Jones, 1993; Gabbott and Bacon, 1996). However,
BMI application was also associated with an increase in activity in a
majority of the FS population as well. Several mechanisms may account
for this effect on these putative inhibitory interneurons. The FS units
that increased their activity may be directly disinhibited by BMI from
other inhibitory interneurons. In fact, large basket cells have been
shown to form a significant percentage of presumed inhibitory contacts
onto the soma of other basket cells, and conversely, GABAergic contacts
have been found on the soma of basket cells (Williams et al., 1992;
Kisvarday et al., 1993). Furthermore, it has recently been shown that
up to two-thirds of this input appears to originate from other
parvalbumin-containing neurons (Gonchar and Burkhalter, 1999), in some
cases resulting in reciprocal connectivity (Tamas et al., 1998). The FS
neurons whose activity increased may also have received feed-forward
disinhibition from excitatory neurons that were themselves
disinhibited. Evidence for feed-forward excitation of local circuit
inhibitory neurons from nearby pyramidal cells has been found from
in vitro dual intracellular recording studies (Thomson and
Deuchars, 1997). Finally, presumed inhibitory autologous synapses
("autapses") have been found to exist on a subpopulation of
cortical inhibitory interneurons (Thomson et al., 1996; Tamas et al.,
1997), and presynaptic GABAA receptors have also
been demonstrated (Vautrin et al., 1994; Xi and Akasu, 1996). BMI
application onto either arrangement should result in the disinhibition
of the presynaptic GABAergic neuron. The mechanisms described above are
not mutually exclusive to one another. In light of the heterogeneity of
the FS population (Kawaguchi, 1993, 1995; Kawaguchi and Kubota, 1997),
a combination of mechanisms is likely to be responsible for the degree
of activation observed in this population.
Tuning loss
A major consequence of the disinhibition resulting from
application of BMI was the loss of tuning in all task phases of both RS
and FS neurons, a result that directly implicates
GABAA-mediated inhibition in both the mnemonic
and sensorimotor phases of the spatial working memory process. This
tuning loss can occur by at least three mechanisms, the first of which
would involve increases in activity for the isodirectional indices
alone. Obviously, if a pharmacological manipulation increased activity
only at the preferred direction, the tuning of the neuron would be
improved (a point we will return to below). However, increases in
activity at the adjacent target locations can cause a loss of tuning by reducing spatial selectivity. A second mechanism would be through increases in activity in a unit's cross-directional indices. This would tend to reduce the overall directionality of a unit's response. Finally, a third mechanism would involve combinations of these two
mechanisms occurring simultaneously. In particular, spatial tuning
could be lost if activity increased equally for all target locations,
thus reducing a unit's signal-to-noise ratio and directional specificity. Examples were found of units that lost their spatial tuning via the second and third mechanisms described above. For example, both the FS unit in Figure 3 and the RS unit in Figure 4 lost
their respective tuning in the drug condition and showed significant
activity increases only in the cross-directional indices; activity in
the isodirectional indices was not changed significantly. However, the
FS unit in Figure 4B lost its tuning by increased activity at both the isodirectional and cross-directional fields. Overall, decreases in cross-directional inhibition, either alone or in
conjunction with decreases in isodirectional inhibition, occurred in
the majority of both RS and FS neurons that lost their tuning (Fig. 7).
Moreover, we never observed a unit losing its spatial tuning solely
through increases in activity in the isodirectional fields. Taken
together, the results demonstrate that both isodirectional and
cross-directional inhibitory mechanisms may play an important role in
the generation of spatially tuned activity in the dPFC during a spatial
working memory task.
Tuning creation
A novel finding of this work was the result that application of
BMI could create statistically significant spatial tuning in a
previously untuned dPFC neuron. As suggested above, this phenomenon was
attributable to isolated increases in activity in one or two adjacent
indices. We hypothesized that such tuning was a result of the
"unmasking" of input that was suppressed in the control condition,
a phenomenon that has been described in sensory cortical areas (Jacobs
and Donoghue, 1991; Eysel et al., 1998). To test this hypothesis, we
assessed the visual field biases of the tuning created with BMI
application. If this tuning was the result of isodirectional
disinhibition, we would expect the visual field tuning biases in each
of the epochs to be in keeping with what is normally found without drug
(Rao et al., 1999). This was, in fact, what we found at both the
population and single unit levels (Figs. 8 and 6, respectively). Thus,
isodirectional inhibition may be playing a role in both shaping spatial
specificity and regulating the threshold of excitatory inputs, allowing
only those of behaviorally appropriate intensity through.
As shown in Figure 2B, the percentage of previously
untuned units that became tuned with the application of BMI increased as the task progressed, becoming maximal in the postsaccadic epoch. In
context of the discussion above, this implies that isodirectional suppression of input itself becomes more prominent as the task progresses, possibly as a result of Post tuning being biased toward the
ipsilateral visual field (Rao et al., 1999). The precise physiological significance of this finding requires further investigation.
Sources of isodirectional and cross-directional inhibition
In previous work, we demonstrated that closely adjacent neurons
possessed tuning similar to one another, suggesting that such neurons
may share common afferent input and thus may form a functional microcolumn, and we also suggested that isodirectional inhibition on a
given unit may arise from nearby microcolumns (Rao et al., 1999). Our
current findings also support the hypothesis that cross-directional inhibition is important for prefrontal working memory function (Goldman-Rakic, 1995b). A significant portion of such inhibition may
originate from the contralateral hemisphere, because several studies
have suggested that prefrontal working memory function is
hemispherically lateralized. Microinjections of dopamine in the dPFC of
monkeys performing the ODR task created mnemonic scotomas primarily in
the contralateral visual field (Sawaguchi and Goldman-Rakic, 1994). It
has also been shown that spatial tuning during the sensory, mnemonic,
and early response phases of the task tends to show a predominantly
contralateral visual field bias (Rao et al., 1999). Furthermore, input
from the contralateral hemisphere has been shown to terminate
ipsilaterally in a columnar manner (Goldman and Nauta, 1977), a result
that may have important consequences for the topography of inhibition
in the dPFC.
Role of inhibition in PFC activity
As we have shown, during the sensorimotor phases of the task,
application of BMI primarily resulted in the loss of previously extant
spatial tuning. Earlier studies have demonstrated that the dPFC
connects primarily to higher order sensory and motor cortical areas
(Goldman-Rakic, 1987) and thus processes highly abstracted information
via its afferent and efferent connections. Hence, one could argue that
de novo creation of spatial selectivity during the
sensorimotor task phases simply for low-level feature detection (as
seen in V1) is redundant, suggesting other roles for the inhibitory
mechanisms in the dPFC. One such role of inhibition in the dPFC may be
attentional control, adjusting the focus of prefrontal cortical
mechanisms to the task at hand. Thus, inhibition may implement part of
the role that has been attributed to the "central executive"
component of working memory (Baddeley, 1992; Goldman-Rakic, 1995a).
The data presented in Figure 2B suggest that mnemonic
activity was the most susceptible to tuning loss by BMI application. It
has been hypothesized that sustained delay period activity is likely to
be at least partially dependent on activation of local or intracortical
recurrent loops (Lisman et al., 1998; Lisman and Fallon, 1999). Such
activity should be, by necessity, heavily regulated by inhibitory
circuitry, a hypothesis that is consistent with models of neocortical
recurrency (Douglas et al., 1995). Hence, such activity should be
highly susceptible to the effects of BMI.
Conclusions
Previous studies of neurons in the dPFC of monkeys by Funahashi et
al. (1989, 1990, 1991) demonstrated that the property of directional
selectivity was not limited to the neurons of the sensory and motor
areas. In the present study, we show that
GABAA-mediated inhibition plays an important role
at the cellular level in the processes underlying spatial working
memory in the dPFC, improving spatial selectivity and possibly playing
critical roles in the attentional control mechanisms of central
executive function.
| |
FOOTNOTES |
Received Aug. 19, 1999; revised Oct. 18, 1999; accepted Oct. 19, 1999.
This work was supported by National Institute of Mental Health Grants
P50 MH44866 and R37 MH3854 (P.S.G.-R.). Further support was provided by
the Medical Scientist Training Program of the National Institutes of
Health (S.G.R).
Correspondence should be addressed to Dr. Srinivas G. Rao, Section of
Neurobiology, Yale University School of Medicine, P.O. Box 208001, New
Haven, CT 06520-8001. E-mail:
srinivas.rao{at}yale.edu.
| |
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S. M. Eggan, T. Hashimoto, and D. A. Lewis
Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia
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[Abstract]
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T. Hashimoto, H. H. Bazmi, K. Mirnics, Q. Wu, A. R. Sampson, and D. A. Lewis
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J. A. Gray and B. L. Roth
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Specificity in Inhibitory Systems Associated with Prefrontal Pathways to Temporal Cortex in Primates
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A. F. T. Arnsten
Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of "Representational Knowledge": A Rational Bridge between Genetics and the Symptoms of Mental Illness
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P. K. Dash, A. N. Moore, N. Kobori, and J. D. Runyan
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S. Kuboshima-Amemori and T. Sawaguchi
Plasticity of the Primate Prefrontal Cortex
Neuroscientist,
June 1, 2007;
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W. B. Wilent and D. A. Nitz
Discrete Place Fields of Hippocampal Formation Interneurons
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S. Bandyopadhyay and J. J. Hablitz
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S. Kroner, L. S. Krimer, D. A. Lewis, and G. Barrionuevo
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T. Karayannis, I. Huerta-Ocampo, and M. Capogna
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Z. Abdul-Monim, J. C. Neill, and G. P. Reynolds
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F. C. Joelving, A. Compte, and C. Constantinidis
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S. M. Eggan and D. A. Lewis
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C. Condy, N. Wattiez, S. Rivaud-Pechoux, L. Tremblay, and B. Gaymard
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D. A. Lewis and B. Moghaddam
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J. H. Krystal, J. Staley, G. Mason, I. L. Petrakis, J. Kaufman, R. A. Harris, J. Gelernter, and J. Lappalainen
{gamma}-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment.
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Z. Delawalla, D. M. Barch, J. L. Fisher Eastep, E. S. Thomason, M. J. Hanewinkel, P. A. Thompson, and J. G. Csernansky
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N.V. Povysheva, G. Gonzalez-Burgos, A.V. Zaitsev, S. Kroner, G. Barrionuevo, D.A. Lewis, and L.S. Krimer
Properties of Excitatory Synaptic Responses in Fast-spiking Interneurons and Pyramidal Cells from Monkey and Rat Prefrontal Cortex
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N. H. Woo and B. Lu
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[Abstract]
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A.V. Zaitsev, G. Gonzalez-Burgos, N.V. Povysheva, S. Kroner, D.A. Lewis, and L.S. Krimer
Localization of Calcium-binding Proteins in Physiologically and Morphologically Characterized Interneurons of Monkey Dorsolateral Prefrontal Cortex
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D. S.F. Ling and L. S. Benardo
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J. P. Tyszkiewicz and Z. Yan
{beta}-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons
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G. Gonzalez-Burgos, L. S. Krimer, N. V. Povysheva, G. Barrionuevo, and D. A. Lewis
Functional Properties of Fast Spiking Interneurons and Their Synaptic Connections With Pyramidal Cells in Primate Dorsolateral Prefrontal Cortex
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T. Hashimoto, S. E. Bergen, Q. L. Nguyen, B. Xu, L. M. Monteggia, J. N. Pierri, Z. Sun, A. R. Sampson, and D. A. Lewis
Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia
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January 12, 2005;
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C. Constantinidis and X.-J. Wang
A Neural Circuit Basis for Spatial Working Memory
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[Abstract]
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H. Trantham-Davidson, L. C. Neely, A. Lavin, and J. K. Seamans
Mechanisms Underlying Differential D1 versus D2 Dopamine Receptor Regulation of Inhibition in Prefrontal Cortex
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November 24, 2004;
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K. Y. Tseng and P. O'Donnell
Dopamine-Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms
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G. Gonzalez-Burgos, L. S. Krimer, N. N. Urban, G. Barrionuevo, and D. A. Lewis
Synaptic Efficacy during Repetitive Activation of Excitatory Inputs in Primate Dorsolateral Prefrontal Cortex
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Q. Xu, I. Cobos, E. De La Cruz, J. L. Rubenstein, and S. A. Anderson
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T. Hashimoto, D. W. Volk, S. M. Eggan, K. Mirnics, J. N. Pierri, Z. Sun, A. R. Sampson, and D. A. Lewis
Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia
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July 16, 2003;
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P. Zhong, Z. Gu, X. Wang, H. Jiang, J. Feng, and Z. Yan
Impaired Modulation of GABAergic Transmission by Muscarinic Receptors in a Mouse Transgenic Model of Alzheimer's Disease
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D. S. Melchitzky and D. A. Lewis
Pyramidal Neuron Local Axon Terminals in Monkey Prefrontal Cortex: Differential Targeting of Subclasses of GABA Neurons
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W.-J. Gao, Y. Wang, and P. S. Goldman-Rakic
Dopamine Modulation of Perisomatic and Peridendritic Inhibition in Prefrontal Cortex
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I. N. Beloozerova, M. G. Sirota, and H. A. Swadlow
Activity of Different Classes of Neurons of the Motor Cortex during Locomotion
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C. F. Bartholomeusz, G. Box, C. Van Rooy, and P. J. Nathan
The modulatory effects of dopamine D1 and D2 receptor function on object working memory in humans
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[Abstract]
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N. Gorelova, J. K. Seamans, and C. R. Yang
Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex
J Neurophysiol,
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[Abstract]
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C. Constantinidis and P. S. Goldman-Rakic
Correlated Discharges Among Putative Pyramidal Neurons and Interneurons in the Primate Prefrontal Cortex
J Neurophysiol,
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G. V. Williams, S. G. Rao, and P. S. Goldman-Rakic
The Physiological Role of 5-HT2A Receptors in Working Memory
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Y. Wang, I. Fujita, H. Tamura, and Y. Murayama
Contribution of GABAergic Inhibition to Receptive Field Structures of Monkey Inferior Temporal Neurons
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L. S. Krimer and P. S. Goldman-Rakic
Prefrontal Microcircuits: Membrane Properties and Excitatory Input of Local, Medium, and Wide Arbor Interneurons
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J. K. Seamans, N. Gorelova, D. Durstewitz, and C. R. Yang
Bidirectional Dopamine Modulation of GABAergic Inhibition in Prefrontal Cortical Pyramidal Neurons
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Z. U. Khan, P. Koulen, M. Rubinstein, D. K. Grandy, and P. S. Goldman-Rakic
An astroglia-linked dopamine D2-receptor action in prefrontal cortex
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TOP
ABSTRACT
INTRODUCTION
