Download Isodirectional Tuning of Adjacent Interneurons and Pyramidal Cells

Isodirectional Tuning of Adjacent Interneurons and Pyramidal Cells
During Working Memory: Evidence for Microcolumnar Organization
in PFC
SRINIVAS G. RAO, GRAHAM V. WILLIAMS, AND PATRICIA S. GOLDMAN-RAKIC
Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510
Rao, Srinivas, G., Graham V. Williams, and Patricia S. GoldmanRakic. Isodirectional tuning of adjacent interneurons and pyramidal
cells during working memory: evidence for microcolumnar organization in PFC. J. Neurophysiol. 81: 1903–1916, 1999. Studies on the
cellular mechanisms of working memory demonstrated that neurons
in dorsolateral prefrontal cortex (dPFC) exhibit directionally tuned
activity during an oculomotor delayed response. To determine the
particular contributions of pyramidal cells and interneurons to spatial
tuning in dPFC, we examined both individually and in pairs the tuning
properties of regular-spiking (RS) and fast-spiking (FS) units that
represent putative pyramidal cells and interneurons, respectively. Our
main finding is that FS units possess spatially tuned sensory, motor,
and delay activity (i.e., “memory fields”) similar to those found in RS
units. Furthermore, when recorded simultaneously at the same site, the
majority of neighboring neurons, whether FS or RS, displayed isodirectional tuning, i.e., they shared very similar tuning angles for the
sensory and delay phases of the task. As the trial entered the response
phase of the task, many FS units shifted their direction of tuning and
became cross-directional to adjacent RS units by the end of the trial.
These results establish that a large part of inhibition in prefrontal
cortex is spatially oriented rather than being untuned and simply
regulating the threshold response of pyramidal cell output. Moreover,
the isodirectional tuning between adjacent neurons supports a functional microcolumnar organization in dPFC for spatial memory fields
similar to that found in other areas of cortex for sensory receptive
fields.
INTRODUCTION
Investigations of spatially tuned neuronal activity promise to
elucidate the respective roles of afferent organization and local
cortical circuitry in the processes underlying regional cortical
function. Directionally selective activity has been observed in
many areas of the brain, from the visual (Hubel and Wiesel
1962) to the prefrontal cortices (Funahashi et al. 1989). Orientation selectivity for bars or edges of neurons in the primary
visual cortex (V1) was originally hypothesized to be the result
of structured excitatory thalamocortical input to this area
(Hubel and Wiesel 1962). However, subsequent work suggested that GABA-mediated inhibition is also involved in the
generation of tuning, although the determination of its precise
role was elusive (Crook et al. 1997; Ferster et al. 1996; Pfleger
and Bonds 1995; Sillito 1984; Somers et al. 1995). One mechanism that was proposed is that of isoorientation inhibition
(Bonds 1989; Ferster 1986; Martin 1988). This is conceptually
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similar to lateral inhibition and refers to the suppression of the
tuned response of a pyramidal neuron by inhibitory interneurons possessing orientation tuning similar but not identical to
that of the pyramidal cell, a process that increases the latter’s
spatial selectivity (Ringach et al. 1997). Another mechanism,
cross-orientation inhibition, refers to the suppression of a pyramidal neuron’s tuned output by inhibitory interneurons possessing directionally opposite tuning (Sillito 1984), thereby
increasing the pyramidal neuron’s signal-to-noise ratio (Wörgötter and Koch 1991). Both mechanisms may operate collectively in the construction of spatial tuning by local circuits in
cerebral cortex (Martin 1988; Wörgötter and Koch 1991).
Spatial tuning was also observed in the dorsolateral prefrontal cortex (dPFC), where it takes the form of the directionally
selective neuronal responses that are observed during tasks that
test spatial working memory. The latter refers to that domain of
memory that transiently holds information “on-line” about the
location of a stimulus relative to retinotopic coordinates until
an appropriate behavioral response is made (Goldman-Rakic
1995). In the oculomotor delay-response (ODR) task, spatially
tuned neuronal activity in dPFC occurs during the sensory
(cue), mnemonic (delay), and motor (response) phases with a
bias for the contralateral visual field (Funahashi et al. 1989 –
1991). Spatially selective delay-period activity, referred to as
the “memory field” of the cell, is thought to represent the
neural substrate for spatial working memory (Funahashi et al.
1989; Goldman-Rakic 1995).
The existence of spatially tuned activity in the prefrontal
cortex during the ODR task raises the question of whether
inhibitory processes play a role in shaping this tuning. If this is
the case, do iso- or cross-directional inhibitory mechanisms
(analogous to iso- and cross-orientation inhibition in V1) play
a role in this process? Further, given the temporal nature of
prefrontal processing, do the roles of these inhibitory mechanisms vary with respect to the different phases of the ODR
task? To address these questions, one must be able to discriminate the response properties of inhibitory interneurons from
pyramidal cells in vivo. Mountcastle et al. (1969) demonstrated
the existence of “regular” and “thin” spikes in extracellular
recording studies of primate cortical neurons and suggested
that these different waveforms corresponded to pyramidal and
“stellate” neuronal morphologies, respectively. Subsequent intracellular work in vitro confirmed the existence of two classes
of action potential waveforms, “regular spiking” (RS) and “fast
spiking” (FS), that differ in their widths and that correspond to
neurons with pyramidal and sparsely spiny stellate morpholo-
0022-3077/99 $5.00 Copyright © 1999 The American Physiological Society
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S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 1. A: schematic of the location of the recording
cylinders (very similar in the 2 monkeys) over the
dorsolateral prefrontal cortex (dPFC), showing their
position centered on the caudal principal sulcus. B:
schematic of the oculomotor delay-response (ODR)
task showing the temporal relationship of the Cue,
Delay, Pre, and Post epochs. A 3.0-s delay is shown,
although both 2.5- and 3.0-s delays were used. Inset:
Cue locations for the 8-target ODR task. All cues were
located at a 13° eccentricity.
gies, respectively (McCormick et al. 1985). FS neurons have
been shown to represent the parvalbumin positive group of
GABAergic interneurons. This class of neuron consists primarily of basket and chandelier cells (Kawaguchi 1995), which
have been shown to provide a major source of inhibitory input
to pyramidal neurons (Gabbott and Bacon 1996; Jones 1993;
Martin et al. 1983; Williams et al. 1992). A number of in vivo
studies utilized the physiological distinction between FS and
RS units recorded extracellularly to discern the functional
properties of putative interneurons and pyramidal cells (Brumberg et al. 1996; Kyriazi et al. 1996; Simons 1978; Swadlow
1995; Swadlow et al. 1998). In the earlier studies by Funahashi
et al. (1989 –1991), the neuronal population was not segregated
into FS and RS units. However, a more recent study in this
laboratory demonstrated inverted patterns of activity between
nearby putative pyramidal cells and interneurons while monkeys engaged in a variety of sensory-guided tasks (Wilson
et al. 1994).
The goal of this study was to explore the contributions that
interneurons and pyramidal cells make to spatial mnemonic
processing in dPFC. To attain this goal, the tuning characteristics of individual neurons within both the FS and RS populations were characterized during the cue, delay, and response
phases of the task. Further, the responses of neurons recorded
simultaneously at the same site (and hence closely adjacent)
were compared to assess the tuning relationships between
FS–RS and RS–RS pairs in mnemonic processing.
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. These animals had undergone
previous surgery under barbituate anesthesia for placement of both a
chronic recording cylinder for acute daily recordings and a scleral eye
coil for detecting eye position. The recording cylinders (19- and
25-mm diam) were positioned over the caudal principal sulcus of the
dPFC by using both X-ray imaging and sterotaxic coordinates (17 mm
lateral and 29 mm anterior to ear-bar zero). A schematic of the
location of the recording cylinders is provided in Fig. 1A (based on the
X-ray photographs and stereotaxic coordinates that were then matched
with the magnetic resonance images of another adult monkey). All
recordings were within 5 mm of the center of the cylinder. Further
anatomic data are not available at this time as the two monkeys are
currently involved in ongoing iontophoretic studies. The cells described subsequently are characteristic of dPFC neurons in that their
functional properties identify them as being engaged in spatial processing, including mnemonic function.
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
The animals were trained in the spatial ODR task shown in Fig. 1B.
The monkey commences each trial by fixating on the central lightemitting diode (LED) for 0.5 s, whereupon a cue LED is illuminated
at one of eight locations with 13° eccentricity and 45° separation for
a period of 0.5 s. After the cue LED extinguishes, a 2.5- or 3.0-s delay
period begins. During both the cue presentation and the delay period,
the monkey is required to maintain central fixation. At the end of the
delay, the central LED extinguishes, and the monkey is required to
make a saccade to the location of the cue shown previously. If the
monkey’s response is completed within 0.5 s of the offset of the
fixation LED and is within 2° of correct location, the trial is considered successful, and the monkey is rewarded with fruit juice. The
position of the cue stimulus is randomly selected for each trial of the
task such that it must be remembered on a trial-by-trial basis. The
monkey’s eye position was monitored with an eye-coil system (CNCEngineering, Seattle, WA), and the ODR task was generated by a
TEMPO system (Reflective Computing, St. Louis, MO).
Neuronal activity was recorded with a carbon-fiber microelectrode,
produced by placing a 20-mm (ELSI, San Diego CA) or 33-mm
(AVCO, Lowell MA) diam carbon fiber in the central barrel of
seven-barrel capillary glass (WPI, Sarasota, FL). This assembly was
then pulled into a microelectrode 60 – 62 mm in length on a custombuilt, computer-controlled microelectrode puller. The tip of the electrode was further fashioned to a length of 20 –50 mm by a combination
of spark etching and beveling on a diamond wheel (Stoelting, Wood
Dale, IL). The low impedance (100 –500 kV) of carbon-fiber electrodes gives them distinct advantages over those made with tungsten,
including exceptionally low-noise (,5 mV pk-pk), improved ability to
record multiple units, and increased sensitivity to smaller neurons
(Armstrong-James and Millar 1979; Fox et al. 1980). Recordings were
made through a custom low-noise amplifier and were band-pass
filtered between ;150 Hz and 12 kHz (4-pole Tchebychev, KrohnHite). The six barrels of the microelectrode were normally filled with
up to three different receptor-specific pharmacological agents that
varied on a monthly basis. However, all data presented in this paper
were acquired only within the drug-free, control condition.
The dura was punctured with a 25-gauge guide tube, and the
electrode was advanced into the brain with a Narishige (Japan) MD-2
digital microdrive. At each recording depth, we generally tested 8 –12
trials of the task at each of the eight cue locations. 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 successfully isolated as many as 5) based on a waveform-matching algorithm. To ensure that units were well isolated, interspike
interval (ISI) histograms were generated for all units that were recorded simultaneously with at least three other units. Given that
cortical neurons can rarely fire at instantaneous rates of .500 Hz
(primarily because of their absolute refractory period), ISI histograms
should not show a significant frequency of counts at #2 ms (Armstrong-James and Fox, 1983). Thus a significant percentage of counts
with such short ISIs is indicative of false-positive errors, i.e., inclusion
of spikes arising from another cell close by. A total of 66 units were
thus analyzed, and we found that the average percentage of spikes that
occurred within 2 ms of the previous spikes was only 0.3% (maximum
for any unit was 2.2%). The average percentage of spikes that occurred within 2.5 ms of a previous spike was only 0.8% (maximum
was 4.0%). Thus even with four or five units being recorded simultaneously all units were well isolated.
In extracellular recordings, the voltage deflections produced by an
action potential approximate to the first-order derivative of the membrane potential (McCormick et al. 1985; Mountcastle 1980), a fact
that was experimentally verified in a study involving simultaneous
intra- and extracellular recording (Matthews and Lee 1991). Therefore
to estimate the intracellularly measured parameter of spike-base width
we measured the elapsed time from the inflection point marking the
beginning of the initial negativity to the return to baseline after the
first positive going deflection (Fig. 2A). Units were categorized as
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being FS based on their short spike-base width (,0.90 ms), relatively
low amplitude, relatively high firing rates, and characteristic sound on
an audio monitor, (McCormick et al. 1985; Mountcastle et al. 1969;
Wilson et al. 1994). Finally, although some RS neurons could be
tracked for several hundred microns, FS cells were rarely tracked for
more than 20 mm, presumably reflecting the large principal apical
dendrites of the former and the smaller soma size and dendritic field
of the latter.
The values that we obtained for the spike-base widths for FS
neurons compared quite well with those measured intracellularly by
McCormick et al. (1985) (0.66 ms 6 0.19 SD vs. 0.67 ms 6 0.16, see
RESULTS). However, the value for the spike-base width that we obtained for RS neurons was considerably shorter than that noted in the
previous study (1.11 ms 6 0.29 vs. 1.74 ms 6 0.41), which may be
due to several reasons. First, our definition of spike-base width represents an approximation to the actual spike-base width as defined
intracellular recordings of membrane potential. Second, in many
cases, it was difficult to define the return to baseline of the positive
deflection for RS neurons because the slope gradually approaches zero
and blends into the baseline noise. A third issue may be signal
filtration, as we used a four-pole Tchebyshev high-pass filter set at
;150 Hz to reduce line noise. This attenuates the low frequencies of
a waveform that are important for defining spike width, an effect that
would tend to be less important for FS neurons because of the
inherently higher frequencies contributing to these waveforms. A final
issue may relate to differences between in vivo versus in vitro physiology relating to PO2, temperature, etc.
Analysis
For purposes of data analysis, each trial in the ODR was divided
into four epochs (Cue, Delay, Pre, and Post), and the average spike
rate across each epoch in a trial was used in subsequent analysis (see
Fig. 1B). The Cue epoch lasts for 0.5 s and corresponds to the stimulus
presentation phase of the task. Delay lasts for 2.5 or 3.0 s and reflects
the mnemonic component of the task. The presaccadic response epoch
Pre starts immediately after the Delay epoch and lasts 0.25 s. As the
name implies, the bulk of the neuronal activity during the Pre epoch
is associated with saccade initiation (Funahashi et al. 1989). Post (the
postsaccadic epoch) starts 0.5 s after the end of Delay and lasts for
0.5 s. By definition, a successful saccade is completed by the time Post
begins. The animal receives its reward 0.50 – 0.55 s after Delay at the
onset of the Post epoch. A given unit can show spatial tuning in any
number of epochs (Funahashi et al. 1989, 1990, 1991), and in this
study all combinations were noted in both the FS and RS populations.
The directionality of a unit’s response in each of the four epochs
was assessed statistically with a vector-algorithm technique that provides a value for the overall strength and direction of tuning. A brief
description follows. As stated earlier, 8 –12 trials were recorded at
each cue location for each neuron. From these data, the individual
trials were arranged into “loops,” where the ith loop was defined as
consisting of the ith trial at each cue location. A loop-vector was then
generated for each of the 8 –12 loops thus created. The magnitudes of
these vectors ranged from 0 to 1 and were defined mathematically
with a measure of circular dispersion (Fisher 1993) to represent the
strength of directionality of the unit’s response within a single loop. A
value of 0 represents a response with no inherent directionality,
whereas a value of 1 represents a highly directional response (i.e.,
firing at only one cue location). The direction of a given loop-vector
indicated the overall preferred firing direction of the unit within that
loop. All the loop-vectors for the cell (within an epoch) were then
added together, and the magnitude was normalized to range from 0 to
1, thus creating a mean resultant vector. Dot products were then
computed between the individual loop vectors and the mean resultant
vector. These dot products provide scalar values that reflect the
contribution each individual loop vector made to the resultant. In a
highly tuned cell all dot products will have a value close to one,
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S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 2. A: example of fast-spiking (FS) and regular-spiking
(RS) spike waveform. The points of measurement for spikebase width and the values for both waveforms are also shown.
B: distribution of spike-base widths for randomly selected FS
and RS neurons. Note that the FS and RS groups form 2
distinct, nonoverlapping populations.
whereas in a poorly tuned cell the dot products will have values that
are much closer to zero. Hence to assess if a unit is tuned we
statistically compared the dot product values with a threshold. This
comparison was effected nonparametrically with the Wilcoxon
signed-rank test (Conover 1971). The values of the dot products were
compared with 10 increasing thresholds ranging from 0 to 0.45, with
increments of 0.05. We then defined a tuning factor (TF) that corresponds to the threshold and that ranges from 0 to 10. A value of 0
indicates that a unit is untuned, e.g., the dot-product values were not
statistically significantly greater than 0. A value of 10, on the other
hand, corresponds to a unit whose dot-product values were significantly greater than a threshold of 0.45. In this way, TF provides a
direct indication of the strength of directionality of a cell during each
epoch, with increasing values of TF corresponding to better tuning.
This vector algorithm was implemented as a C11 program, which
takes as input intermediate files created by a Spike2 script and creates
an output file, which is then imported directly into a database created
in Filemaker from Claris (Santa Clara, CA). Other analyses and
graphs were generated with Statview (Abacus Concepts, Berkeley,
CA) and Deltagraph (DeltaPoint, Monterey, CA), respectively.
We first examined the visual field biases (proportions tuned in the
2 halves of the visual field) and TFs of the FS and RS neuronal
populations during the four task epochs. The next step in the analysis
involved looking for within-cell differences in directional tuning
between epochs for individual FS and RS neurons. This analysis was
performed by first finding neurons that showed statistically significant
tuning in at least two epochs, e.g., Cue and Post. The tuning angle of
one epoch is then subtracted from the other, and the resulting value is
normalized between 0 and 180°, thus making irrelevant the order of
subtraction. This manipulation was carried out in a pairwise manner
for all epochs: Cue, Delay, Pre, and Post. Depending on the number
of epochs in which a unit was tuned, as many as six groups of
difference data were generated for each unit: Cue versus Delay, Cue
versus Pre, Cue versus Post, Delay versus Pre, Delay versus Post, and
Pre versus Post. This procedure effectively renders the data linear and
thus allows for the subsequent use of statistical analysis techniques
that are otherwise inappropriate for circular data (Fisher 1993). The
distributions of these within-cell tuning differences were visualized
with histograms with three discrete intervals corresponding to the
angle ranges 0° . . . ,60°, 60° . . . ,120°, 120° . . . 180°.
The final step in the analysis was to look for across-pair differences
in directional tuning for each epoch, examining both FS–RS and
RS–RS pairs. (Pairs of FS neurons are a relatively uncommon occurrence, a fact that prevented us from doing any statistical analysis on
them.) Pair analysis was performed in a manner analogous to that used
for determining between-epoch differences in tuning described previously. A pair of simultaneously recorded neurons showing tuning in
the same epoch (e.g., Cue) is first found, and then the tuning angle of
one unit is subtracted from the other. This value is then normalized to
the range of 0 –180°. Again because of normalization the order of
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
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FIG. 3. The visual field bias of each of the
4 epochs for FS and RS neuronal populations.
The percentage of each type of neuron tuned
in a particular epoch as well as the average
value of the TF are shown adjacent to the bar
plots of the corresponding epochs. A test of
proportion was used to detect statistically significant bias, and the results are indicated
above each bar graph (* indicates significance
with P , 0.05). Note the relative consistency
in the percentage of tuned neurons in each
epoch for the FS and RS neuronal populations.
Also note the gradually shift from contralateral to ipsilateral tuning during successive epochs present in both neuronal populations, a
result that is particularly striking in the FS
neuron population.
subtraction is not important. This technique was used to compare on
an epoch-by-epoch basis the responses of multiple neurons, taken
pairwise, recorded simultaneously at the same site. Once again, to
visualize the differences in tuning across neurons, histograms were
generated with angle ranges 0° . . . ,60°, 60° . . . ,120°, 120° . . .
180°. We defined the 0°. . . ,60° range as reflecting isodirectional
activation or inhibition, depending on whether we were referring to
RS–RS or FS–RS pairs, respectively. Likewise, the 120° . . . 180°
range was defined as reflecting cross-directional activation or inhibition. Finally, the 60° . . . ,120° range represents a region of intermediate directionality.
To analyze the nature of any connectivity that was shared or
occurred between units in a pair we examined the cross-correlation
histograms (obtained from Spike2 analysis) of the two cells within the
pair for signs of 1) feedforward excitation (a peak occurring with short
latency after a spike in the other cell, reflecting the rise time of an
excitatory postsynaptic potential) (Cope et al. 1987; Matsumara et al.
1996), 2), feedforward inhibition (a dip with a short latency, reflecting
the duration of an inhibitory postsynaptic potential) (Aertsen and
Gersten 1985; Aertsen et al. 1992), and 3), shared afferent input (a
peak centered on the time of origin of a spike in the other cell) (Bryant
et al. 1973; Moore et al. 1970). The cross-correlograms were obtained
by analyzing the firing patterns of the two cells across an entire
experiment without regard for task epochs or stimulus presentation.
Hence commonly used techniques to assess temporal coherence (such
as the shuffle predictor method) were not applicable (Nowak and
Bullier 1998). Further, a detailed cross-correlation analysis was beyond the scope of this study and was limited by the spike detection
process used (while a template match is in process for 1 spike
waveform, another spike waveform cannot be detected on the same
channel). See Nowak and Bullier (1998) for a complete review of this
technique.
RESULTS
RS and FS populations
A total 144 FS and 382 RS neurons were recorded from,
including 82 FS–RS pairs and 86 RS-RS pairs, in the two
monkeys. The waveforms of representative RS and FS neurons are shown in the Fig. 2A. The spike-base widths for 19
FS and 17 RS neurons selected randomly are shown in Fig.
2B. As described in METHODS, the mean and SD values for
spike-base width were 0.67 ms 6 0.16 and 1.11 ms 6 0.29
for FS and RS neurons, respectively. This difference in the
mean values of the spike-base width was significant by
unpaired t-test (P , 0.00001).
Seventy-one percent (270/382) of RS neurons and 69%
(99/144) of FS neurons were tuned (i.e., TF . 0, see METHODS)
in at least one epoch. Figure 3 shows the percentages of RS and
FS neurons that were tuned in each epoch as well as the visual
field bias (i.e., the relative proportions being tuned in the
ipsilateral and contralateral visual fields) and TFmean of each
population. The proportions of the RS and FS neurons tuned in
each epoch were remarkably consistent across the two populations. Further, the visual field bias of the two populations did
not differ significantly from each other within any one epoch
[test of 2 proportions (TP) (Welkowitz et al. 1982): maximum
z 5 1.826 in Pre] nor were differences found in the magnitude
of TF between FS and RS neurons by factorial analysis of
variance (ANOVA), either taken overall (overall TFmean: FS 5
1.85, RS 5 2.03; P 5 0.292) or on an epoch-by-epoch basis
(minimum P 5 0.1503 for Pre). Also for both RS and FS
neuronal populations taken individually there were no statistically significant differences by factorial ANOVA in the values
of TFmean between epochs (P 5 0.260).
An example of an FS neuron showing spatially tuned activity throughout the ODR task is shown in the rastergrams and
summed histograms of Fig. 4A. This neuron was consistently
activated in the contralateral (right) visual field at 45° and 90°
during the Cue, Delay, and Pre epochs. However, typical of the
FS population shown in Fig. 3, the cell then underwent a
complete inversion of tuning (by 167°), exhibiting robust postsaccadic activation at 225° and 270° in the ipsilateral visual
field. Further, in all epochs one can appreciate the suppression
of activity in directions opposite to those in which the unit
showed its maximal response. Figure 4B shows the same data
in mean and SE format, with the results of tuning analysis by
the vector algorithm for each epoch superimposed. The results
of the analysis confirm the observations noted above.
Analysis of FS–RS and RS–RS pairs
A major goal of this study was to determine the functional
relationships between adjacent neurons with respect to the
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S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 4. A: example of an FS neuron that showed spatially tuned responses in all task phases, presented in rastergram and
histogram format. Activity in the Pre and Post epochs is indicated by the shaded and solid bars, respectively, in the overlying trial
bar. Note the consistency in tuning direction present during the Cue, Delay, and Pre epochs as well as the inversion of tuning that
occurs between the Pre and Post epochs. B: same unit shown in mean and SE in polar plots with superimposed tuning analysis
results. The change in tuning angles between successive epochs is indicated by the value shown between them. Scale for the radial
direction for spike rate is indicated on plot. Scale for the tuning analysis vectors is 10. The spontaneous activity for this cell was
3.4 6 0.7 spikes/s.
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
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FIG. 5. Across-pair epoch comparisons for FS–RS (top)
and RS–RS (bottom) pairs. In FS–RS pairs, the predominant
relationship in firing between the cells is isodirectional. However, during Post a significant amount of cross-directional
firing relationship is present. A x2 done between the distributions of the Pre and Post epoch data for the FS–RS pairs was
significant with P , 0.05.
development of spatial tuning in dPFC. Accordingly, we
investigated the differences in spatial tuning between neurons recorded simultaneously at the same site. We found an
overwhelming tendency for isodirectional relationships in
tuning between members of such pairs, whether they were
FS–RS or RS–RS. As shown in Fig. 5, during the Cue,
Delay, and Pre epochs, .70% of units in FS–RS pairs and
.60% of units in RS–RS pairs showed directions of tuning
within 60° of one another, indicating a predominant, isodirectional relationship between these cells. Note that FS–FS
pairs also showed isodirectionality in five cases but never
exhibited a cross-directional relationship in a total of nine
pairs where both units were tuned during the same epoch. To
determine whether such isodirectional processing arose
from feedforward connectivity between adjacent cells or
from sharing spatially specific inputs arising from the same
network, simple cross-correlations were performed on 56
pairs, focusing on those showing tuning during the Cue
epoch (when presumably the cells might be sharing similar
inputs). Remarkably, no cross-correlations indicative of
feedforward inhibition were found within any pair of cells,
whereas feedforward excitation was evident between two
RS–RS pairs and one FS–RS pair (from RS to FS). The
cross-correlations indicative of feedforward excitation in
the RS–RS pair are shown in Fig. 6A, and those in an FS–RS
pair are shown in Fig. 6B. It can be seen in both histograms
that a sharp peak arises with a latency of ,2 ms after the
occurrence of a spike in the other member of the pair.
Cross-correlations indicative of shared excitatory afferents
were found in 15 pairs (1 FS–FS, 3 FS–RS, and 11 RS–RS).
A good example of this effect in RS–RS pairs was found at
one site where four units were recorded simultaneously and
only one of which was untuned during the Cue period. As
shown in Fig. 6C, positive cross-correlations showing coincidence of long-lasting rise in spiking were found among the
three tuned neurons but did not include the untuned RS cell
(RS1). Thus, at least in this simple cross-correlation analysis, a considerable number of cells recorded at the same site
appears to share their afferent input, and in rare cases RS
units provide feedforward excitation to their immediate
neighbors, whether RS or FS.
The isodirectional relationship between units in FS–RS
pairs was found to dissociate at the end of the task. Thus the
differences in tuning angles between FS and RS neurons
during the Post epoch distributed almost evenly between the
0 – 60° range (47%) and the 120 –180° range (41%), reflecting both iso- and cross-directional relationships, respectively (Fig. 5). The differences in distribution between the
iso- and cross-directional data for the Pre epoch data versus
Post data were significant (x2 P , 0.05). Further analysis of
the units constituting the FS–RS pairs in Post revealed that
the FS units in such pairs show predominantly ipsilateral
visual field tuning regardless of whether they belonged to an
iso- or cross-directional pair (Fig. 7). RS neurons in an
isodirectional pair also show a predominantly ipsilateral
visual field bias; however, RS units in a cross-directional
pair tended to show a contralateral visual field bias. A
comparison of the visual field preferences of the RS neurons
in the iso- and cross-directional pairs was significant (x2,
P 5 0.0187). These results indicate that a subset of RS
neurons that remains contralaterally tuned in Post is responsible for the cross-directional relationship with their FS
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S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 6. Cross-correlation histograms for closely adjacent cells recorded simultaneously. A: example of feedforward excitation
between 2 RS units, RS1 showing a transient peak at 1.6 ms after a spike (at the time of origin) in RS2. B: similar example of
feedforward excitation, but this time between an RS unit and an FS unit, with a peak at 1.8 ms. When the template-matching
algorithm is in progress for 1 spike, another spike cannot be detected. This produces the gap in spike counts of ;1–2 ms. C:
cross-correlations among 4 RS units recorded at the same site. Unit 1 was untuned, but units 2– 4 were well tuned during Cue,
within a few degrees of each other. The cross-correlations among units 2– 4 show clear signs of synchronization related to sharing
afferent input (probably to a high degree) (Shadlen and Newsome 1998), but there was no evidence of cross-correlation between
unit 1 and the other units. The positive cross-correlations show rather broad peaks probably because of the bursting pattern of firing
of these cells that could be seen in their autocorrelations. Also there was no evidence of any feedforward excitation between these
cells when examined on a time-base similar to that in A and B.
neighbors. An example of an FS–RS pair showing an isodirectional relationship in the Pre epoch (54°) and a crossdirectional relationship in the Post epoch (143°) is shown
in Fig. 8 in mean and SE format. The FS neuron in this
pair shows a tuning shift of 94° between Pre and Post,
whereas the tuning of the RS neuron only shifts by 5°
between these two epochs. The FS neuron becomes ipsilat-
eral in its tuning during Post, whereas the RS neuron remains contralaterally tuned. In contrast to the FS–RS pairs,
RS–RS pairs maintained their isodirectional relationship
in tuning throughout all epochs of the trial. Accordingly,
no significant difference between the distributions of the
Post epoch and the Pre epoch was found in these pairs
(x2 P . 0.05).
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
TABLE 1.
neurons
1911
Within-cell comparisons for regular- and fast-spiking
Comparison
n
RS, Du
n
FS, Du
Cue vs. Delay
Cue vs. Pre
Cue vs. Post
Delay vs. Pre
Delay vs. Post
Pre vs. Post
53
41
53
48
49
58
41.6 6 5.9°
56.7 6 6.9°
97.2 6 7.8°
40.7 6 6.1°
100.4 6 7.0°
88.3 6 7.5°
19
15
18
10
18
20
41.7 6 10.0°
77.5 6 13.6°
111.2 6 12.3°
56.4 6 15.8°
118.4 6 11.9°
94.9 6 13.9°
Values are means 6 SE.
FIG.
7. An examination of the visual field preferences of the FS–RS pairs
showing iso- and cross-directional inhibition in the Post epoch previously in
Fig. 6. No difference was found between the FS neurons in the two groups;
however, the RS neurons that were in the isodirectional group were ispilaterally tuned, whereas those in the cross-directional group were contralaterally
tuned.
Tuning shifts across task epochs
A previous study by Funahashi et al. (1991) observed that
the prefrontal neuron’s preferred direction often shifted between the sensory and responses epochs of the task. We examined this tendency in the FS and RS populations and found
that both classes of neurons exhibited similar shifts in visual
field preference as the task progressed. During stimulus presentation (Cue epoch), a significantly larger proportion (by a
test of proportional significance) (Welkowitz et al. 1982) of
both the RS (71%) and especially the FS (81%) populations
was tuned toward the visual field contralateral to the hemisphere of our recording sites. This contralateral visual field bias
continued throughout the mnemonic component of the task
(Delay epoch) in both populations; however, the bias was not
as pronounced as that observed in Cue (67% of FS units and
61% of RS units). The results of the within-cell analysis are
shown in Table 1, and the distribution of Cue versus Delay (as
well as Cue vs. Pre and Cue vs. Post) is plotted in histogram
format for both FS and RS neurons in Fig. 9. It is apparent from
these analyses that there was a high degree of similarity (i.e.,
remaining #0 – 60°) in the direction of tuning between the Cue
and Delay epochs for both FS (68%) units and RS (79%) units.
Both of the response-associated epochs Pre and Post were
different from the sensorimnemonic epochs in several respects.
First, a higher percentage of FS and RS neurons exhibited
tuning in Post compared with the preceding epochs (54% of RS
units and 49% of FS units). Second, although RS neurons
continued to display a contralateral visual field bias during Pre,
FS neurons lost their bias and underwent a significant shift in
their tuning angles from that observed in the delay period (x2
P 5 0.0457). Therefore this shift in tuning in the FS population
occurred before the saccadic response at the end of the Pre
epoch. Finally, by the Post epoch the RS units lost their visual
field bias, a result that was consistent with a significant shift in
visual field bias observed between Pre and Post (x2 P 5
FIG. 8. An example of an FS–RS pair showing an
isodirectional tuning relationship in the Pre epoch and a
cross-directional tuning relationship in the Post epoch.
The data are presented as mean and SE data in polar plots
with superimposed tuning analysis results. The differences in tuning directions in the Pre and Post epochs
between the FS and RS neuron is shown between the
polar plots for the corresponding epochs. Scale for the
radial direction for spike rate is indicated on plot. Scale
for the tuning analysis vectors is 5. Spontaneous activity
was 3.5 6 0.4 spikes/s for unit1 and 4.7 6 0.8 spikes/s
for unit4.
1912
S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 9. Histograms of the Cue vs. Delay, Cue vs. Pre, and Cue
vs. Post within cell epoch comparisons for FS and RS neurons. It
can be seen that the shifts in tuning noted at the population level
in Fig. 3 were also observed within individual FS units (seen first
between Cue and Pre) and RS units (between Cue and Post). A
test of proportion between the percentage of Cue vs. Pre data
located between 120 and 180° of FS and RS neurons was significant with P , 0.05, whereas a corresponding test done for Cue
vs. Post was not.
0.0044) for these units. However, FS units now showed a
significant tuning bias toward the ipsilateral visual field, despite the fact that in the Post epoch the eye position is uncontrolled as the trial is complete.
These shifts in visual field bias noted at the population level
were confirmed by analysis of the within-cell differences in
tuning between epochs shown in Table 1 and Fig. 9. For both
FS and RS units, the disparity in tuning direction between the
Cue and Post epochs was significantly greater than that between the Cue and Delay epochs (posthoc Scheffe: RS, P ,
0.0001; FS, P 5 0.0095). It is apparent from the posthoc results
of the ANOVA and from Fig. 9 that a shift in visual field bias
occurred within individual FS and RS neurons as the trial
progressed. A significantly higher proportion of FS units (27%)
showed inversion of tuning (i.e., a shift in angle by 120 –180°)
between Cue and Pre than did RS units (7%). By Post, however, a large proportion of both RS and FS units showed an
inversion of their tuning compared with that in Cue (41 and
61%, respectively).
DISCUSSION
Inhibitory mechanisms in working memory
The role of inhibition in the construction of receptive field
properties has been intensively studied in the visual system, particularly with regard to orientation selectivity. However, evidence
ranges from inhibition having “no role in the creation of orientation selectivity” to inhibition “being the architect of orientation
selectivity” (Ferster 1986; Sillito 1984). Consensus appears, not
surprisingly, to be in between (Hata et al. 1988; Martin 1988).
Several modeling studies confirmed the importance of inhibition
in the creation of tuning. For example, Wörgötter and Koch
(1991) hypothesized a combination of iso- and cross-orientation
inhibition for the optimal construction of spatial tuning.
The prefrontal cortex has been shown to have structural
organization not unlike that of the primary visual cortex, including a columnar organization of inputs such as those from
posterior parietal cortex (Goldman-Rakic and Schwartz 1982)
and the contralateral hemishphere (Goldman and Nauta 1977).
A number of anatomic studies have described the types of
interneurons present in primate prefrontal cortex as well as
their connectivity to pyramidal and spiny-stellate interneurons
(Gabbott and Bacon 1996a,b; Jones 1993; Thomson et al.
1996). In this study, the interneurons thought to be represented
by FS units were clearly distinguished from RS units that are
considered to represent pyramidal or spiny-stellate cells. The
FS waveform has been shown in vitro to be highly characteristic of parvalbumin-positive basket and chandelier cells
(Kawaguchi 1995). Although these neurons are thought to
represent ;25% of the total interneuron pool, they can have a
profound effect on pyramidal neuron output caused by the
pattern of their connectivity with pyramidal neurons (Gabbott
and Bacon 1996a,b; Martin et al. 1983; Thomson et al. 1996).
A major finding of this study is that putative basket and chandelier cells in the primate prefrontal cortex show tuned sensory,
mnemonic, and response related activity very similar to that of
putative pyramidal cells. Moreover, these FS cells show a great
propensity to be isodirectional in tuning with closely neighboring
RS cells before the completion of a mnemonically guided saccadic response. This evidence suggests that at least one subset of
interneurons plays an integral and dynamic role in the local
circuits engaged by working memory in prefrontal cortex and is
spatially specific in regulation of pyramidal cell firing. Therefore
inhibitory processes may be an important component of the functional organization of the underlying circuitry that shapes spatially
tuned activity in dPFC.
FS and RS neuronal populations
Both FS and RS neurons showed a contralateral visual field
bias at the start of the trial during the Cue epoch, and both
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
populations showed a progressive shift in tuning from the
contralateral toward the ipsilateral visual field during the
course of the trial. At both the beginning and end of the trial
(the Cue and Post epochs, respectively), the FS population
showed a greater degree of lateralization than did RS neurons.
By examining the differences in the tuning among successive
task epochs of individual neurons, we found that the visual
field shift noted at the population levels appears to be a result
of individual neurons progressively shifting their tuning preferences during the course of a trial. Such an effect would have
important consequences for the population vector encoded by
the output of the pyramidal cells. Within a given epoch of the
ODR task, shifts in the direction of the population vector are
primarily the result of different dPFC neurons being activated
for the different stimulus locations, as is the case in the primate
motor cortex (Georgopoulos et al. 1982, 1986). However, in
contrast to the motor cortex (Georgopoulos et al. 1989), shifts
in the direction of the population vector occurring as a trial
progresses appears to be the result of individual neurons shifting direction.
Our finding of a contralateral field bias for RS neurons
during Cue, Delay, and Pre is consistent with work of Funahashi et al. (1989 –1991), which revealed a progressively
smaller contralateral visual field bias at the population level as
the trial progressed. This suggests that the findings of Funahashi et al. were primarily representative of the pyramidal
cell population, a result that is not surprising considering that
pyramidal cells constitute a large majority of prefrontal cortical
neurons. Funahashi et al. also noted that postsaccadic activity
often showed tuning in the opposite direction to that of preceding epochs. In particular, in cells with memory fields,
postsaccadic activity often occurred in the opponent direction
and coincided with a return of delay activity to baseline (Funahashi et al. 1989, 1991). This inversion of tuning was confirmed by this study for a subset of RS neurons. Moreover, we
also found this inversion to be present for the majority of FS
neurons. Note that eye position is not controlled in the postsaccadic epoch as the trial is complete. However, regardless of
eye position, the previously predominantly isodirectional tuning relationship changes, indicating that FS and RS neurons
respond differentially before and after the goal-directed saccade. The changes in tuning noted in the Post epoch indicate
that the nature of postsaccadic activity varies within the RS
population. One subset of RS neurons was found to invert their
tuning in Post and become ipsilaterally tuned. This subset may
be involved in the generation of eye movements opposite to
that encoded in the presaccadic epoch, i.e., returning fixation to
the center. Alternatively, they may have a function more intrinsic to the working memory process, e.g., serving to extinguish the encoding of the current target in memory. The other
subset of RS cells did not show inversion and instead remained
tuned contralaterally. This subset may serve to help maintain
attention on a target that is associated with reward and thus
may be part of a process that supports the working memory
function (Funahashi et al. 1993). That pairs of RS cells do not
show cross-directional relationships may be because they are
functionally coupled in local pyramidal cell clusters without
inhibitory intermediaries (Kritzer and Goldman-Rakic 1995).
These issues require further investigation.
The increased role of cross-directional inhibition seen in
FS–RS pairs in Post point to a dynamic role of inhibitory
1913
mechanisms in the dPFC, shifting with real-time events occurring during cognition. Part of this shift takes place during the
task, when interneurons show a significant rotation of their
tuning angle between the delay and presaccadic epoch. This
phenomenon may be the result of a new source of afferent
input to dPFC, possibly related to the GO signal provided by the
offset of the fixation spot. One source of such input that was
previously suggested is the thalamus (Funahashi et al. 1991;
Goldman-Rakic 1995). Alternatively, the cross-directional input may also arise from the contralateral hemisphere, as a great
deal of evidence points to a hemispheric organization of prefrontal cortical function (Goldman and Nauta 1977; Hughes
and Peters 1992; McGuire et al. 1991a,b; Sawaguchi and
Goldman-Rakic 1994).
Iso- and cross-directional mechanisms
Our findings that neurons recorded at the same site tended to
share very similar angles of tuning regardless of the direction
of the cue stimulus may appear to contradict those of an earlier
study in this laboratory (Wilson et al. 1994), which showed
inverted patterns of stimulus-specific responses between FS
and RS cells in the inferior convexity. However, an important
methodological difference between these two studies arises
from the distance between the units constituting the pairs being
analyzed. The previous work considered as pairs any two
neurons located #400 mm of one another, a distance that may
in fact cross functional columnar boundaries within the prefrontal cortex (Goldman and Nauta 1977; Leichnetz 1980;
Schwartz et al. 1988). Such a columnar effect was indicated by
a combined single unit recording and optical imaging study in
inferotemporal cortex (Wang et al. 1996), which demonstrated
the regional clustering of cells responding to similar features in
“spots” of ;500 mm in diameter. Thus from the results of the
previous study of FS and RS units it was inferred that “distal”
(i.e., hundreds of micrometers away) cross-directional inhibition between functionally opponent columns may exist in
dPFC (Goldman-Rakic 1995). We considered only neurons
simultaneously recorded at a single site and hence closely
adjacent to one another to constitute pairs. Considering the size
of our recording tips and the fact that previous anatomic studies
suggested a size of 50 – 60 mm on center for microcolumns
(Peters and Kara 1987), it is likely that we recorded from
within one or between two adjacent microcolumns within the
same functional column. Thus we submit that isodirectional
tuning is an important phenomenon for closely adjacent units,
and this has important implications for local lateral inhibitory
mechanisms.
In the light of these hypotheses, we propose a model of
inhibitory local circuits in dPFC in which the processes involved in spatial tuning are dependent on the distance between
interneurons and their target cells, particularly pyramidal neurons. Specifically, we propose that isodirectional inhibition
prevails within a functional column, whereas cross-directional
inhibition is exerted primarily between functional columns in
primate prefrontal cortex. As depicted in Fig. 10 (top left), a
functional organization of closely spaced microcolumns provides an ideal framework for isodirectional relationships
among neurons, whether they reside within or between the
microcolumns inside a single functional column. The probable
anatomic substrate for this circuitry is illustrated (Fig. 10, top
1914
S. G. RAO, G. V. WILLIAMS, AND P. S. GOLDMAN-RAKIC
FIG. 10. A model of iso- and cross-directional inhibition in dPFC. Top left: hypothetical circuit demonstrating isodirectional
tuning relationships between adjacent microcolumns with small differences (;5°) in
their directional preferences and (bottom)
cross-directional relationship between distant, functionally defined macrocolumns
with a wide difference (;120 –180°) in their
directional preference. The bulk of interactions is considered likely to take place in
layer III, where a large proportion of horizontal connections and parvalbumin-positive interneurons can be found. Top right:
section from dPFC showing 5-HT2A–like
immunoreactivity in prefrontal cortex (courtesy of Robert Jakab) in which bundles of
apical dendrites ascend from clusters of
large pyramidal cells in layer V, previously
described as the principal components microcolumns in visual cortex (Peters and Kara
1987). Bottom inset: autoradiographic visualization of the columnar organization of
afferent input (corresponding to functional
macrocolumns) to the principal sulcus of the
monkey (courtesy of Goldman-Rakic) after
injection of tritiated leucine into the contralateral hemisphere.
right) in the form of regularly dispersed dendritic bundles
arising from clusters of cells representing microcolumns in the
dPFC of rhesus monkeys similar to those in rat visual cortex
first described by Peters and Kara (1987). The isodirectionality
observed between members of FS–RS and RS–RS pairs during
much of the task can be interpreted as implying the existence
of a local cortical unit of spatial processing, with RS and FS
neurons becoming synchronously entrained as a result of connectivity (DeFelipe et al. 1990; Mountcastle 1997). Our crosscorrelation analysis of paired units supports the interpretation
that closely adjacent neurons within the same microcolumn
may share a high proportion of their spatially tuned afferents
(Matsumura et al. 1996; Shadlen and Newsome 1998; Swadlow et al. 1998) and thus form a strong consensus in tuning
preferences (a form of neural averaging) (see Zohary et al.
1994). Indeed, no evidence was found of feedforward inhibition in cross-correlations between simultaneously recorded FS
and RS units, indicating a lack of functional inhibition between
closely adjacent cells. However, isodirectional inhibition could
occur between microcolumns, consistent with the findings of
Thomson and coworkers (1996, 1997), who reported considerable inhibition between FS interneurons and pyramidal cells
at distances of ;50 –250 mm. The differences in consensus of
tuning between neighboring microcolumns may therefore provide the circuit basis for isodirectional inhibition, which serves
to sharpen spatial tuning in a mechanism similar to that pro-
posed for visual cortex (Crook et al. 1997; Kisvarday et al.
1994; Peres and Hochstein 1994; Ringach et al. 1997; Somers
et al. 1995; Worgotter and Koch 1991).
In the model illustrated in Fig. 10 (middle) cross-directional
inhibition may predominate between functional columns that
contain microcolumns possessing considerably different directional preferences, a situation similar to ocular dominance and
orientation columns in visual cortex described by Hubel and
Wiesel (1977). The anatomic basis for the columnar organization of dPFC is clearly illustrated (Fig. 10, bottom) by the
spatial distribution of afferents to the principal sulcus from the
contralateral hemisphere. In keeping with this model, it has
been shown that basket cells project to nearby isooriented sites
at 100 – 400 mm as well as to more distant cross-oriented sites
400 – 800 mm away (Kisvarday et al. 1994). These columnar
dimensions are in good accord with those reported for interdigitating columnar projections to the principal sulcus (Goldman-Rakic and Schwartz 1982) originating from the contralateral hemisphere and the posterior parietal cortex. Taken as a
whole, the evidence supports a microcolumnar organization of
functionally grouped neurons in prefrontal cortex, which serve
to enhance the resolution of stimulus encoding and/or retrieval
in the working memory process.
We thank H.-C. Leung for advice on the development of the vector algorithm and L. Nowak for advice on the cross-correlation analysis.
ISODIRECTIONAL RELATIONSHIP BETWEEN MICROCOLUMNS
This work was supported by National Institute of Mental Health Grants P50
MH-44866 and R37 MH-3854 to P. S. Goldman-Rakic. Further support was
provided by the Medical Scientist Training Program of the National Institutes
of Health to S. G. Rao.
Address for reprint requests: P. S. Goldman-Rakic, Section of Neurobiology, Yale University School of Medicine, P. O. Box 208001, New Haven, CT
06520-8001.
Received 21 July 1998; accepted in final form 13 November 1998.
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