Neuromodulation of prefrontal cortex in non-human primates by dopaminergic receptors during rule-guided flexible behavior and cognitive control.
Vijayraghavan S, Major AJ, Everling S (2017) Frontiers in Neural Circuits. 1:91. doi: 10.3389/fncir.2017.00091
The oculomotor system is the most thoroughly understood sensorimotor system in the brain, due in large part to electrophysiological studies carried out in macaque monkeys trained to perform ocuolomotor tasks. A disadvantage of the macaque model is that many cortical oculomotor areas of interest lie within sulci, making high-density array and laminar recordings impractical. Many techniques of molecular biology developed in rodents, such as optogenetic manipulation of neuronal subtypes, are also limited in this species. The common marmoset (Callithrix jacchus) possesses a smooth cortex allowing easy access to frontoparietal oculomotor areas, and may bridge the gap between systems neuroscience in macaques and molecular techniques. Techniques for restraint, training,and neural recording in these animals have been well developed in auditory neuroscience. Those for oculomotor neuroscience, however, remain at a relatively early stage. Here we provide details of a custom-designed restraint chair for marmosets, a combination head restraint/recording chamber allowing access to cortical oculomotor areas and providing stability suitable for eye movement and neural recordings, as well as a training protocol for oculomotor tasks. We additionally report the results of a psychophysical study in marmosets trained to perform a saccade task using these methods, showing that, as in rhesus and humans, marmosets exhibit a “gap effect” – a decrease in reaction time when the fixation stimulus is removed prior to the onset of a visual saccade target. These results are the first evidence of this effect in marmosets, and support the common marmoset model for neurophysiogical investigations of oculomotor control.
Acetylcholine is released in the prefrontal cortex and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of prefrontal cortex during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral prefrontal cortex (DLPFC) of male rhesus macaques performing rule-guided pro- and antisaccades, a well-established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, while the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to non-specific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers.
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.
Methods for chair restraint and training of the common marmoset on oculomotor tasks
Johnston K, Barker K, Schaeffer L, Schaeffer D, Everling S (in press) Journal of Neurophysiology
Cholinergic overstimulation attenuates rule selectivity in macaque prefrontal cortex.
Major AJ , Vijayraghavan S, Everling S (in press ) J. Neurosci.