Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control

Abstract

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease.

Keywords: antisaccades; cognitive control; dopamine receptors; neuropharmacology; nonhuman primates; prefrontal cortex; rules; working memory.

Figure 1

Effects of dopamine D1 receptor (D1R) blockade and stimulation in caudal dorsolateral prefrontal cortex (PFC) on oculomotor delayed response. (A) Local injections of D1R antagonist, SCH23390, induce deficits in contralateral memory-guided saccades, but not in visually guided saccades (Left panel; individual solid black lines are traces of correct saccades; dashed lines are erroneous saccades. Left most subpanels are control; right most sub panels are after drug injection. Top panels are during memory-guided saccade performance. Bottom panels are during control visually guided saccade performance with zero delay). Right panels show time course of drug-induced changes in angular dispersion of contralateral memory-guided saccades (top subpanel) and saccade reaction times (bottom subpanel). Panels adapted with permission from Sawaguchi and Goldman-Rakic (1991). (B) Local injections of D1R agonist, SKF81297, induce deficits in contralateral memory-guided saccades. Red traces show correctly executed saccades, green traces show error saccades (top panel, control; second panel, injection of 10 μl saline; third panel, infusion of 10 μl SKF81297; bottom panel, visually-guided saccades after SKF81297 injection). D1R stimulation, but not saline, induced increases in spatial dispersion of memory-guided saccades, but not visually-guided saccades to the contralateral target. Adapted from Gamo et al. (2015).

Figure 2

Effects of D1R blockade in frontal eye field (FEF) on saccade target selection and FEF modulation of V4 stimulus responsiveness. All panels adapted with permission from Noudoost and Moore (2011a). (A) Top panel shows the free-choice saccade task. Two stimuli are presented with varying temporal difference between their onsets. One stimulus is in the response field of the neuron recorded from the FEF area where pharmacological manipulations were performed. The monkey can freely choose between the two targets. Bottom panel shows the effects of D1R blockade on saccade choice. Traces (black, control; orange, drug) show the proportion of saccade choices towards the FEF response field for different temporal differences in onset of stimuli. D1R blockade increased the proportion of made towards the response field of the FEF area that was manipulated, thereby increasing contralateral saccade target selection. (B) Normalized stimulus-induced activity of V4 neurons with the same response field as the pharmacologically manipulated FEF area (black, control; orange, drug) increased after D1R blockade in FEF. (C) Orientation tuning of V4 neurons (black, control; red, drug) was augmented after FEF D1R blockade.

Figure 3

Effects of dopamine receptor manipulations on PFC activity encoding rules in a numerosity judgment task. All panels adapted with permission from Ott et al. (2014). (A) Rule-guided numerosity judgment task used in Ott et al. (2014). Macaques had to use a rule (“greater than” or “less than”) cued by a colored dot or drops of juice to determine if a test numerosity panel displayed after a delay had more or less dots than a previously presented sample numerosity panel. The animals responded by holding or releasing a lever, based on their trial numerosity judgment. (B) Effects of D1R stimulation (top panel), D1R blockade (middle panel) and D2 receptor (D2R) stimulation (bottom panel) on normalized activity of PFC neurons showing differential responses to the trial rule. D1R stimulation and D2R stimulation augmented selectivity in rule representation, while D1R blockade suppressed population rule selectivity.

Figure 4

Effects of D1R agonist and D2R agonist on population activity of PFC neurons recorded during the performance of the rule-guided pro- and antisaccade task. All panels adapted with permission from Vijayraghavan et al. (2016). (A) Recording locus (left) and the pro- and antisaccade task are shown. Subjects maintained central fixation, and a briefly presented colored cue indicated the rule to employ in the trial. This information was maintained in working memory (WM). After a brief gap post-fixation point offset, a peripheral stimulus was presented and monkeys had to use the previously remembered rule to make a saccade towards or away from the stimulus. In another version of the task employed in Vijayraghavan et al. (2016), the rule was uncued and the subjects had to derive the trial rule based on reward feedback and maintain this rule was a block of trials. Blocks of prosaccade trials alternated with blocks of antisaccade trials and the subjects learned to switch response types based on feedback. (B) D1R stimulation (left panel) with iontophoresis of full D1R agonist SKF81297 suppressed the population activity of PFC neurons, while D2R stimulation with D2R agonist quinpirole (right panel) increased population activity.

Figure 5

Effects of D1R stimulation on rule selectivity of PFC neurons. All panels adapted with permission from Vijayraghavan et al. (2016). (A) Iontophoretic stimulation of D1R (middle panel) suppressed the activity of a PFC neuron that had more prestimulus activity during prosaccade trials. Rule selectivity of the neuron was diminished, and recovered upon cessation of drug application (bottom panel). Blue traces and rasters: prosaccade trials; Red traces and rasters: antisaccade trials. (B) D1R stimulation decreased PFC population rule selectivity (top panel) assessed by signal detection theory. The area under the receiver operating characteristic curve (AUROC) for individual rule-selective neurons tested is plotted for control (abscissa) and during D1R stimulation (ordinate). Drug application shifted the AUROCs below the equality line (dashed line) indicating reduction in population rule selectivity. D1R stimulation at both low and high doses reduced population rule selectivity, with greater reduction for higher doses (bottom panel). Blue dots represent neurons with greater activity for the prosaccade rule and red dots, neurons with greater activity for the antisaccade rule.

Figure 6

Effects of D2R stimulation on perisaccadic activity of PFC neurons during pro- and antisaccades. All panels adapted with permission from Vijayraghavan et al. (2016). (A) Trial rasters and mean spike density functions for a PFC neuron with elevated perisaccadic activity for contralateral saccades are shown. D2R stimulation increased the activity of the neuron, but had a greater effect on perisaccadic discharges during prosaccade trials (left; dark blue, contralateral prosaccade; light blue, ipsilateral prosaccade) than during antisaccade trials (right; dark red, contralateral antisaccade; light red, ipsilateral antisaccade). (B) Sliding population saccade selectivity analysis shown for 35 PFC neurons with contralateral saccade selectivity. D2R stimulation increased saccadic selectivity prior to saccade onset (dashed line) for prosaccades, but not antisaccades. Saccade selectivity was not appreciably affected after the saccade. (C) Population saccade selectivity in the presaccadic epoch was increased for prosaccades but not for antisaccades after D2R stimulation (control, black; gray, drug).