Cholinergic modulation of working memory activity in primate prefrontal cortex

Abstract

The prefrontal cortex, a cortical area essential for working memory and higher cognitive functions, is modulated by a number of neurotransmitter systems, including acetylcholine; however, the impact of cholinergic transmission on prefrontal activity is not well understood. We relied on systemic administration of a muscarinic receptor antagonist, scopolamine, to investigate the role of acetylcholine on primate prefrontal neuronal activity during execution of working memory tasks and recorded neuronal activity with chronic electrode arrays and single electrodes. Our results indicated a dose-dependent decrease in behavioral performance after scopolamine administration in all the working memory tasks we tested. The effect could not be accounted for by deficits in visual processing, eye movement responses, or attention, because the animals performed a visually guided saccade task virtually error free, and errors to distracting stimuli were not increased. Performance degradation under scopolamine was accompanied by decreased firing rate of the same cortical sites during the delay period of the task and decreased selectivity for the spatial location of the stimuli. These results demonstrate that muscarinic blockade impairs performance in working memory tasks and prefrontal activity mediating working memory.

Fig. 1.

Behavioral task. Successive frames represent sequence of stimulus presentation on the screen. A: delayed response task. The cue is followed by a delay period, after which the monkey needs to saccade to the location of the remembered cue. B: 1 distractor stimulus appears after the cue. C: 2 distractor stimuli appear after the cue. D: spatial match/nonmatch task. Two stimuli are presented in sequence, and the monkey is required to saccade to a green choice target if they are the same or a blue choice target if they are different.

Fig. 2.

Behavioral performance. Percentage of correct trials is plotted as a function of scopolamine dose for each stimulus type and monkey. Data are shown from trials during which neural recordings were obtained. A and B: behavioral performance of the 2 monkeys tested in the delayed response task with 0, 1, and 2 distractors and in the visually guided saccade (VGS) task. C: behavioral performance of 1 monkey in the match/nonmatch task.

Fig. 3.

Error analysis. Histogram represents the types of errors and corresponding error rates in the delayed response task. Data are averaged from both monkeys and all doses shown in Fig. 2 (which involved an unequal number of sessions). Plots represent end point of saccades for control and scopolamine conditions in delayed response trials with 0, 1, and 2 distractors (gray squares). Data from 1 monkey are shown from trials collected during neural data acquisition. In all trials shown, the cue (black square) appeared at the bottom of the screen. Only trials that resulted in errors are depicted. End points of saccades that landed near the cue location may still have resulted in errors if the monkey did not fixate on that location for at least 0.2 s after the saccade. A lower density of points in the scopolamine condition is the result of fewer sessions collected under drug administration.

Fig. 4.

Anatomical localization. A: lateral view of the monkey brain. Area sampled is indicated in gray. AS, arcuate sulcus; PS, principal sulcus. B and C: electrode grid and recording sites for the monkeys tested with the chronic implant. Black circles represent sites with stimulus responses; filled circles represent sites with delay period activity, used in analysis.

Fig. 5.

Population responses following the best cue location. A and B: population peristimulus time histograms (PSTHs) from the control and scopolamine conditions, respectively, recorded from the chronic implant. Data are averaged from trials without any distractors. The fixation (FIX) period, cue presentation, and delay period are indicated. Dotted lines represent the baseline firing rate during the 1 s of the fixation period. Shaded areas represent delay period activity exceeding the baseline. D and E: population PSTH from the control and scopolamine conditions, respectively, recorded with single electrodes. C and F: cumulative discharges during the trial for the 2 tasks. Baseline firing rate has been subtracted from each curve.

Fig. 6.

Population responses for best and opposite location. A and B: population PSTHs from the control and scopolamine conditions, respectively, recorded in the match/nonmatch task. Fixation period, cue presentation, and delay period are indicated. Yellow arcs represent the receptive field (for illustration purposes; this varied for each neuron). Responses are shown following a cue in the best location, followed by a nonmatch stimulus at the opposite location, similar to Fig. 5, D and E (which averaged responses from all trials, regardless of where the nonmatch stimulus appeared). C: responses in the control condition with the cue appearing opposite to the best receptive field location, followed by a nonmatch at the best location. Strong anticipatory activity is evident before the appearance of the nonmatch stimulus. D: responses from the scopolamine condition. Significantly lower levels of anticipatory activity were detected.