Attenuation of Delay-Period Activity of Monkey Prefrontal Neurons by an
2-Adrenergic Antagonist During an Oculomotor Delayed-Response Task
T. Sawaguchi
Department of Psychology, Hokkaido University, Sapporo 060-0810; and Department of Behavioral and Brain Sciences, Primate Research Institute, Kyoto University, Inuyama, Aichi 484, Japan
 |
ABSTRACT |
Sawaguchi, T. Attenuation of delay-period activity of monkey prefrontal neurons by an
2-adrenergic antagonist during an oculomotor delayed-response task. J. Neurophysiol. 80: 2200-2205, 1998. To examine the role of norepinephrine receptors in spatial working memory processes mediated by the prefrontal cortex (PFC), noradrenergic antagonists (yohimbine for
2, prazosin for
1, and propranolol for
receptors) were applied iontophoretically to neurons of the dorsolateral PFC in rhesus monkeys that performed an oculomotor delayed-response (ODR) task. The ODR task was initiated when the monkeys fixated on a central spot on a computer monitor and consisted of fixation (1 s), cue (1 of 4 peripheral cues, 0.5 s), delay (fixation cue only, 4 s), and go periods. In the go period, the subject made a memory-guided saccade to the target location that was cued before the delay period. I focused on 49 neurons that showed directional delay-period activity, i.e., a sustained increase in activity during the delay period, the magnitude of which varied significantly with the memorized target location. Iontophoretic (usually 50 nA) application of yohimbine, but not prazosin or propranolol, significantly decreased the activities of most of the neurons with directional delay-period activity (n = 41/49, 81%). Furthermore, yohimbine attenuated the sharpness of tuning, examined by a tuning index, of delay-period activity and had a greater attenuating effect on delay-period activity than on background activity. These findings suggest that the activation of
2-adrenergic receptors in the dorsolateral PFC plays a modulatory role in neuronal processes for visuospatial working memory.
 |
INTRODUCTION |
The dorsolateral prefrontal cortex (PFC) of primates is involved in visuospatial working memory (for reviews see Funahashi and Kubota 1994
; Goldman-Rakic 1987
, 1995
), and a subset of the neurons in this area shows a "memory field" that represents visuospatial working memory processes (Funahashi et al. 1989
). Whereas dopamine was the focus of interest in uncovering the neurochemical basis of this cognitive function (Sawaguchi and Goldman-Rakic 1994
; Sawaguchi et al. 1988
, 1990a
,b
; Williams and Goldman-Rakic 1995
), another major catecholamine, norepinephrine, and its
2-adrenergic receptors in the dorsolateral PFC were also implicated in working memory by several lines of studies (Arnsten and Goldman-Rakic 1985
; Li and Mei 1994
; for a review, see Arnsten et al. 1996
). However, it is almost completely unknown how
2-adrenergic receptors are involved in neuronal processes for visuospatial working memory mediated by the dorsolateral PFC.
I combined iontophoretic application of norepinephrine antagonists (yohimbine for
2, prazosin for
1, and propranolol for
receptors) with single-neuron recording during an oculomotor delayed-response (ODR) task in monkeys. The ODR task is sensitive to visuospatial working memory, and a subset of PFC neurons shows "directional delay-period activity," which is considered to represent a memory field for visuospatial working memory processes (Funahashi et al. 1989
). I found that antagonism of
2-adrenergic receptors preferentially attenuates directional delay-period activity in neurons of the dorsolateral PFC, suggesting that the activation of
2-adrenergic receptors in the dorsolateral PFC plays a modulatory role in neuronal processes for visuospatial working memory.
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METHODS |
Three male rhesus monkeys (Macaca mulatta, ~4.5-6.5 kg, KA, NA, and TA) were trained to perform an ODR task (Fig. 1A). During sessions, the monkey sat in a monkey chair and faced a multiscan 21-in. cathode ray tube monitor (PC-TV471, NEC, Tokyo) placed ~60 cm in front of him. The ODR task was started when the monkey fixated on a central spot (
, 0.2° × 0.2°) on the monitor. One second later, a visual cue (
, 0.5° × 0.5°) was presented for 0.5 s, followed by a delay period. The cue was presented randomly at one of four peripheral locations (right, 0°; up, 90°; left, 180°; down, 270°) with an eccentricity of 15°. After a delay period of 4 s, the fixation spot was extinguished, which instructed the monkey to make a memory-guided saccade to the location that was cued before the delay period (go period). A correct response was rewarded by a drop of water 0.2 s after the response. Trials were separated by an intertrial interval of 2 s. The task and the recordings were controlled by a system consisting of an infrared eye-camera system (R-21 C-A, RMS, Hirosaki, Japan), two personal computers (PC9801 FE and PC9801 BX, NEC, Tokyo) that were networked by RS232C and parallel I/O, and other associated peripherals. Throughout the experiment, the subjects were treated in accordance with the Guide for Care and Use of Laboratory Animals (National Institutes of Health) and the Guide for Care and Use of Laboratory Primates (Primate Research Institute, Kyoto University, Japan).

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| FIG. 1.
A: oculomotor delayed-response (ODR) task used in the present study, which required monkeys to make a memory-guided saccade to a remembered target location (right, up, left or down; 15° in eccentricity) that was cued before a brief delay period of 4 s. B: points of penetration of the micropipette illustrated on the surface of the left PFC. Data from 3 hemispheres were combined based on cortical sulci. PS, principal sulcus; AS, arcuate sulcus.
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The iontophoretic technique and the method used to analyze neuronal activity were similar to those described in our previous studies (Sawaguchi 1987
; Sawaguchi et al. 1990a
). Briefly, multibarreled glass micropipettes were used for extracellular recording of neuronal activity and iontophoretic application of drugs. The central barrel of the micropipette, which contained a carbon-fiber filament (7-µm diam; T-300, Toray, Tokyo), was filled with 0.9% saline and used to record neuronal activity. The surrounding barrels were filled with, and used for iontophoretic application of, solutions of the following drugs: yohimbine hydrochloride (0.01 M, pH 5-6; Research Biochemicals International, Natick, MA), prazosin hydrochloride (0.01 M, pH 5-6; Research Biochemicals International), propranolol hydrochloride (0.01 M, pH 5-6; Research Biochemicals International), 0.9% saline (to balance the current), and other drugs such as SCH23390 and ketanserin for other studies (monkey TA was also used for studies other than the present iontophoretic studies). While the monkey was performing the ODR task, the extracellular activity of single neurons was recorded with the micropipette. The neuronal activity was converted from A/D by a window-discriminator (DIS-1, BAK Electronics, Germantown, MD) for analysis with a personal computer. Raster displays and time histograms, aligned at the onset of task periods, were constructed by the computer (usually, with a sampling rate of 50 ms), and the discharge rate during each period in the task was compared with the background discharge rate during the intertrial interval. When a neuron's discharge rates during both the early and latter halves (2 s, respectively) of the delay period were significantly higher than the background discharge rate (Mann-Whitney U test, P < 0.05), it was considered to show delay-period activity. Furthermore, when the delay-period activity of such a neuron differed significantly with the direction of the target (1-way analysis of variance, ANOVA, P < 0.05), it was judged to show directional delay-period activity. The activity of each task-related neuron was recorded for >16 successive trials, and then each of the drugs was applied with a current of 30-90 nA (usually 50 nA) for >16 successive trials to examine the influence of the drug on task-related neuronal activity. When the overall discharge rate of a neuron during task trials changed significantly during the application of a drug (P < 0.05), the neuron was judged to be responsive to the drug. This comparison was performed with a Student's t-test; when there was a significant difference in variance, the Aspin-Welch method was used for correction. Drug applications were separated by >2 min to allow for the recovery of neuronal activity. To prevent leakage of the drugs, a backing current (2-5 nA) was applied continuously during the predrug control period and between drug applications through the tip of each barrel containing drug solution. Neuronal activity could be recorded stably for several trials, and there were no obvious changes in the shapes of spikes that appeared during drug application (see Sawaguchi et al. 1990a
). Furthermore, to identify the frontal eye field (FEF), intracortical microstimulation (ICMS, 11 or 22 cathodal pulses of 0.2-ms duration at 333 Hz,
100 µA) was applied through the tip of the electrode; when eye movements were elicited by ICMS at a certain site, the site was considered to be located in the FEF. The present data are for neurons located rostral to the FEF.
After extensive testing, the monkeys were deeply anesthetized with an overdose of pentobarbital sodium and perfused with physiological saline followed by formalin. The cortical surface was examined to detect the points of penetration. Figure 1B illustrates the sites of penetration, at which the present data were obtained, on the surface of the left hemisphere. The sites on the right hemisphere were homotopically transferred to the left side. Overall, 20 penetrations were made in the dorsolateral PFC of four hemispheres of the three monkeys (both hemispheres for monkey KA, left hemisphere for monkey NA, and right hemisphere for monkey TA). The points were scattered throughout the caudal one-half of the periprincipal sulcal area and the immediately adjacent cortex in the PFC, which has cytoarchitectural features of Walker's area 46 (Walker 1940
).
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RESULTS |
Of the 87 neurons recorded during ODR task performance, I concentrate here on 49 neurons that showed directional delay-period activity, i.e., a sustained increase in activity during the delay period, the magnitude of which differed significantly with the direction of the target, because such activity is considered to represent a memory field at the neuronal level for visuospatial working memory processes in which it plays a central role (Funahashi et al. 1989
). Iontophoretic application of yohimbine with a 50-nA current attenuated the activities of most of these neurons (n = 41/49, 84%), and directional delay-period activity appeared to become diffuse during such application. Application with a higher current intensity (i.e., 30 nA vs. 50 nA and/or 50 nA vs. 90 nA, tested for 8 neurons) had a greater attenuating effect on the activities. In contrast with yohimbine, iontophoretic application of prazosin or propranolol with a 50-nA current had no clear effect on most of the neurons tested (n = 11/14 and n = 17/19, respectively), and the results with these drugs will be described only briefly.
An example of the effect of yohimbine on a neuron with directional delay-period activity is shown in Fig. 2. Figure 2A shows averaged histograms and raster displays for predrug control activity and for activity with the iontophoretic (50-nA) application of yohimbine. Figure 2B shows polar plots of delay-period activity together with the background discharge rate (solid cross). This neuron showed a sustained increase in activity during the delay period, particularly for trials with the right target location (i.e., 0° in polar coordinates). The discharge rate during the delay period differed significantly with the target direction (mean ± SD spikes/s; 13.3 ± 7.6 for right-target trials, 7.4 ± 5.1 for upper-target trials, 6.4 ± 6.0 for left-target trials, 8.7 ± 6.3 for down-target trials; ANOVA, P < 0.001). Iontophoretic (50 nA) application of yohimbine significantly decreased the overall activity during task trials (8.3 ± 5.9 vs. 4.7 ± 4.3; t-test, P < 0.001) as well as delay-period activity (9.1 ± 6.8 vs. 4.8 ± 4.1; P < 0.001). The background activity during the intertrial interval was also decreased (6.5 ± 6.3 vs. 5.0 ± 4.3; P < 0.05), although to less of a degree than delay-period activity (i.e.,
23% vs.
47% for average delay-period activity for all directions and
23% vs.
62% for the right direction, which was associated with the maximal delay-period activity). Furthermore, the directional difference in delay-period activity became insignificant during the application of yohimbine (5.1 ± 3.8 for right-target trials, 4.7 ± 3.7 for upper-target trials, 4.6 ± 4.6 for left-target trials, 4.8 ± 4.2 for down-target trials; ANOVA, P = 0.89, NS). Indeed, the significant increase in activity during the delay period for right-target trials was almost completely inhibited to close to the background discharge rate during the application of yohimbine.

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| FIG. 2.
A: effect of iontophoretic application of yohimbine on a prefrontal cortex (PFC) neuron with directional delay-period activity during performance of the ODR task. Raster displays and averaged histograms, which are aligned by the events that comprise the task, for the activity before (control) and during the application of yohimbine with a 50-nA current are shown. The activities associated with different target locations (right, 0°; up, 90°; left, 180°; down, 270°) are illustrated separately. F, fixation period; C, cue period; D, delay period; G, go period from the onset of the go signal to the onset of reward delivery. Vertical scale, 10 spikes/s. B: polar plots of the delay-period activity shown in A. The mean discharge rate during the delay period and background discharge rate (solid cross) are plotted for each direction. TI, value of the tuning index.
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To further examine the characteristics of the effect of yohimbine on directional delay-period activity, a tuning index (TI) was calculated as follows
where "preferred" is the average discharge rate during the delay period for the preferred direction associated with the maximal delay-period activity and "unpreferred" is that for the unpreferred direction (usually opposite the preferred direction) associated with the minimal delay-period activity; for 13 neurons it was significantly lower than the background activity (P < 0.05), which is consistent with data reported by Funahashi et al. (1989)
. Thus, TI quantitatively represents the sharpness of the tuning of directional delay-period activity; its ranges from 0 to 1, and larger values indicate greater sharpness of such tuning. For the neuronal activity shown in Fig. 2, TI was greatly decreased by yohimbine (~86%), from 0.35 for predrug control activity to 0.05 for activity with yohimbine (Fig. 2B). In Fig. 3A, the TI value with yohimbine is plotted against the predrug TI value for each neuron (n = 41) whose overall activity was significantly decreased by the iontophoretic (50 nA) application of yohimbine. Most of the data points are located below the 45° angle, indicating that TI was decreased during the application of yohimbine for most of the neurons. The average difference in TI values between predrug activity and activity with yohimbine was statistically significant (mean ± SD, 0.21 ± 0.09 vs. 0.08 ± 0.07, paired-t-test, P < 0.001). Furthermore, to examine the degree to which yohimbine affected delay-period activity and background activity, I compared the percent changes in the discharge rate during the delay period (relative to predrug control activity) during the application of yohimbine with the changes in the background activity for neurons affected by yohimbine. In Fig. 3B, the percent changes in the discharge rates during the delay period are plotted against the percent changes in the background activity for these neurons. The data for delay-period activity are for the preferred direction. As shown in Fig. 3B, most of the data points fall below the 45° line, indicating that the application of yohimbine had a greater attenuating effect on delay-period activity than on background activity. In about one-fourth of the neurons (n = 10/41, 24%), background activity was either increased (n = 3) or not affected (n = 7) by yohimbine, although it significantly decreased delay-period activity. On average, the percent decrease in delay-period activity was significantly greater than the percent change in background activity (
57.3 ± 22.7% vs.
35.3 ± 28.2%, paired-t-test, P < 0.001). Thus, yohimbine significantly attenuated the tuning index of directional delay-period activity and had a greater attenuating effect on this activity than on background activity.

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| FIG. 3.
A: effect of iontophoretic (50 nA) application of yohimbine on the tuning index for PFC neurons that showed directional delay-period activity. The values of the tuning index with yohimbine are plotted against those without it for neurons whose activities were significantly affected by the application of yohimbine. Most of the data points are located below the 45° line, indicating that yohimbine decreased the tuning index for most of the neurons. B: percent changes in the discharge rate caused by the iontophoretic (50 nA) application of yohimbine for delay-period activities and background activities. The percent changes in the discharge rate during the delay period are plotted against those of the background activity for the neurons affected by yohimbine. Most of the data plots fall below the 45° line, which indicates that yohimbine had a greater attenuating effect on delay-period activity than on background activity for most of the neurons.
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To examine the pharmacological specificity of yohimbine, propranolol and prazosin were also applied to some of the neurons with directional delay-period activity. Typical data are shown in Fig. 4. Only the activities for the preferred direction are shown for simplicity (i.e., right direction for Fig. 4A and upper direction for Fig. 4B). Figure 4A shows a typical result with propranolol. Iontophoretic (50 nA) application of yohimbine significantly decreased the activity of this neuron, and the extent of the decrease was greater with a 50-nA current than with a 30-nA current, i.e., the effect of yohimbine was dose dependent (average discharge rate, mean ± SD spikes/s, 8.9 ± 5.67 for predrug control trials; 3.2 ± 1.9 for yohimbine with a 50-nA current, P < 0.001, compared with the control; 4.9 ± 3.7 for yohimbine with a 30-nA current, P < 0.001, compared with the control, P < 0.001, compared with yohimbine with a 50-nA current). However, the application of propranolol with a 50-nA current did not significantly affect the activity (9.1 ± 5.7 with propranolol, NS, compared with the control). Propranolol was tested in 19 neurons with directional delay-period activity and had no clear effect on most of the neurons tested (n = 17/19). Furthermore, as with propranolol, iontophoretic (50 nA) application of prazosin also had no clear effect on the activities of most of the neurons tested (n = 11/14). Figure 4B shows a typical result with prazosin. Iontophoretic application of yohimbine with 50 nA significantly decreased the activity of this neuron (10.6 ± 5.6 for predrug control vs. 6.9 ± 4.2 for yohimbine, P < 0.001). In contrast, application of prazosin with a 50-nA current had no significant effect (9.7 ± 6.5, NS, compared with the control).

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| FIG. 4.
Effects of iontophoretic application of propranolol (A) and prazosin (B) on the activity of 2 different PFC neurons that were affected by yohimbine. Raster displays and averaged histograms, aligned by the events of the task, for the activity before (control) and during drug application are shown. Only the activities associated with the preferred direction (i.e., right for A and up for B) are illustrated for simplicity. F, fixation period; C, cue period; D, delay period; G, go period from the onset of the go signal to the onset of reward delivery.
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DISCUSSION |
Noradrenergic antagonists were applied iontophoretically to neurons of the dorsolateral PFC in monkeys that performed an ODR task that is sensitive to visuospatial working memory. Iontophoretic application of a selective
2-adrenergic receptor antagonist, yohimbine, attenuated the sharpness of tuning of directional delay-period activity and had a greater attenuating effect on this activity than on background activity. Because directional delay-period activity was demonstrated to represent a "memory field" of PFC neurons for visuospatial working memory processes (Funahashi and Kubota 1994
; Funahashi et al. 1989
; Goldman-Rakic 1995
), the current findings suggest that the activation of
2-adrenergic receptors plays a modulatory role in maintaining and/or facilitating the memory field of PFC neurons during ODR performance. Without sufficient activation of
2-adrenergic receptors in the dorsolateral PFC, neuronal processes that are critical for visuospatial working memory should be attenuated. However, because yohimbine also attenuated the background activity for most of the neurons with directional delay-period activity, the modulatory role of
2-adrenergic receptors appears to be modest.
Both norepinephrine-containing fibers and
2-adrenergic receptors are prominent in the dorsolateral PFC of primates (Goldman-Rakic et al. 1990
; Lewis and Morrison 1989
). A behavioral pharmacological study (Arnsten and Goldman-Rakic 1985
) demonstrated that intramuscular injection of the
2-adrenergic receptor agonist clonidine improved performance in a manual delayed-response task in aged monkeys. This improvement was antagonized by yohimbine, and the effect of clonidine disappeared when the dorsolateral PFC was surgically removed. Furthermore, intracerebral infusion of yohimbine into the PFC of monkeys appears to impair the performance of a manual delayed-response task (Li and Mei 1994
). More recently, we reported that local injection of yohimbine, but not prazosin or propranolol, into the dorsolateral PFC of monkeys induced a specific deficit in ODR performance (Sawaguchi and Kikuchi 1997
). These findings are consistent with these earlier results and provide significant evidence of a modulatory role of
2-adrenergic receptors in neuronal processes for visuospatial working memory mediated by the dorsolateral PFC. Because dysfunction of
2-adrenergic receptors in the PFC is evident in working memory deficits that accompany some mental disorders, such as schizophrenia and Korsakoff's amnesia as well as aging (Arnsten and Goldman-Rakic 1985
; Arnsten et al. 1996
), the current data may be useful for understanding at the cellular level cognitive deficits/declines associated with such mental disorders and aging. However, because another major catecholamine dopamine and its D1-family of receptors appear to also play a critical role in PFC functions for visuospatial working memory (Sawaguchi and Goldman-Rakic 1994
; Sawaguchi et al. 1988
, 1990a
,b
; Williams and Goldman-Rakic 1995
), further studies are required to differentiate the possible different roles of
2-adrenergic receptors and D1-family dopamine receptors in working memory processes mediated by the dorsolateral PFC.
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ACKNOWLEDGEMENTS |
The author thanks K. Watanabe-Sawaguchi and I. Yamane for assistance with the animal care and experiments.
This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (No. 08680889 in 1996-1997), funds from the Akiyama-Memorial Foundation (1997), and the Human Frontier Science Program RG-16/93.
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FOOTNOTES |
Address for reprint requests: Dept. of Psychology, Hokkaido University, N10 W7, Kita-ku, Sapporo 060-0810, Japan.
Received 8 December 1997; accepted in final form 16 June 1998.
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