Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex.

Acetylcholine is released in the prefrontal cortex (PFC) 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 PFC 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 PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades 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, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific 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.