Interactions between prefrontal cholinergic and glutamatergic signaling support attentional function

Attentional processes and capacities are central to cognitive performance. Cortically projecting cholinergic neurons of the basal forebrain are essential components of the neural systems underlying attentional function; however exactly how the cholinergic system supports attentional performance remains unknown. Our current model suggests that transient (scale of seconds) increases in acetylcholine (ACh) release in the prefrontal cortex foster the detection of predictive cues, and that the generation of such transients is dictated by glutamate released from mediodorsal thalamic afferents and the stimulation of ionotropic glutamate receptors. The studies that informed this model were based on data from anesthetized preparations and animals performing relatively simple instrumental tasks. Two of the primary aims of the work going in to my dissertation were to utilize a novel technique with a high degree of temporal precision to record glutamatergic and cholinergic activity in animals performing a sustained attention task (SAT) to characterize how these two major neurotransmitter systems interact to support attentional performance. The major results from these studies are that in contrast to signal detection per se, transient increases in ACh release mediate performance on signal trials requiring a shift from cue-independent to cue-dependent processing. The pattern of glutamate release in task performing animals suggests that in addition to recruiting cholinergic mechanisms, glutamate plays an additional role in signaling choice. Finally our work revealing the interactions between cholinergic and glutamatergic mechanisms additionally predict and explain the observation that alpha4beta2 nAChR agonists more robustly enhance attentional performance in the distractor version of the SAT than the non-selective nAChR agonist nicotine. The results from these studies suggest the limited beneficial effects of nicotine are due to its stimulation of long lasting release events that are unlikely to support specific cognitive operations. Collectively, the work included here has 1) redefined the role of cholinergic transient in attention 2) begun to explore the complex interplay between glutamatergic and cholinergic signaling in cognitive performance 3) demonstrated that by building upon our knowledge of the functions of and interactions between these two systems we can predict the pro-attentional efficacy of putative cognition enhancers.