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.
Highlights
The prefrontal cortex (PFC) is a critical node in brain networks involved in complex cognitive functions and has undergone a great evolutionary expansion in primates (Wise, 2008)
We examined the effects of D1 receptor (D1R) and D2 receptor (D2R) stimulation on the activity of dorsolateral PFC neurons engaged in this task
When we examined the selectivity for the trial rule in the delay period, higher doses of D1R stimulation disrupted overall rule selectivity of the population of ‘‘rule neurons’’ that distinguished between proand antisaccade task rules in their activity (Figure 5)
Summary
The prefrontal cortex (PFC) is a critical node in brain networks involved in complex cognitive functions and has undergone a great evolutionary expansion in primates (Wise, 2008). The Arnsten group has subsequently shown that D1Rs co-localize on dendritic spines with HCN channels and blockade of the HCN current could reverse D1R physiological suppression of PFC neurons (Gamo et al, 2015) In contrast to these physiological effects of D1Rs during spatial WM, relatively little is known about the physiological role of D2Rs. One clue emerged when iontophoresis of a D2R blocker and stimulator selectively disrupted and augmented, respectively, the activity of PFC neurons that discharge during the saccadic response epoch of memory-guided saccades, while sparing the persistent activity of ‘‘delay’’ neurons firing in the memory period prior to the response (Wang et al, 2004). It is necessary to examine the influence of dopaminergic modulation on post-response, and intertrial activity, a theme which we will elaborate on further
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