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.

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

“…Embryos lacking HTT have disrupted PRC2mediated regulation of gene expression (Seong et al, 2010). Similar to our findings in Htt cKOs, PRC2 loss-of-function in SPNs leads to neurodegeneration (Von Schimmelmann et al, 2016). Therefore, Htt loss in SPNs may disrupt PRC2-dependent regulation of SPN-specific genes.…”

“…Some axonal TdTomato signal was observed in the GPe of D1-Cre mice, because DP-SPNs send axon collaterals through the GPe (Figure 1E, top;Cazorla et al, 2014). A2A-Cre expression was restricted to IP-SPNs; however, D1-Cre-expressing cells were present in the cortices of D1-Cre mice, because subsets of cortical neurons express the dopamine receptor D1 (Vijayraghavan et al, 2017). We found that $15% of layer 2/3, $15% of layer 4, and $40% of layer 5/6 NeuN + neurons express D1-Cre in the M1 motor cortex, which harbors pyramidal neurons that project to dorsal striatum that is affected in HD (Figures S1A-S1C).…”

Extra-striatal D2/3 receptor availability in youth at risk for addiction

“…Cortical DA transmission sustains neural activity, facilitating the planning of complex behavioral sequences, impulse control, and reward processing [ 11 , 17 ]. Though most attention has been paid to cortical DA 1 receptors, accumulating evidence indicates that DA 2/3 Rs also modulate cortical cell excitability, influencing perseverative behaviors and behavioral inhibition, perhaps through actions on subcortical projection sites [ 11 , 49 ]. The elevated cortical DA 2/3 R availability in our high-risk youth might aggravate susceptibility to these maladaptive behaviors, as greater PFC DA 2/3 R-mediated neurotransmission has been associated with impulsive behaviors in laboratory animals [ 50 ].…”

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

“…The executive attention network is a neural network involving the anterior cingulate cortex and prefrontal cortex while various memory processes also include brain regions such as the prefrontal cortex, hippocampus, and entorhinal cortex. Pharmacological manipulation of dopaminergic tone and receptors impacts cognitive capacities [5]. Genetic variation in dopaminergic genes is associated with cognitive performance in both healthy and clinical populations [6][7][8].…”