The pleiotropic effects of ACh on cortical circuits described above are likely to underlie its ability to modulate cognitive behaviors. In rodents, lesions of cholinergic inputs to the cortex impair tests of sustained attention, particularly across sensory modalities (McGaughy et al., 2002; McGaughy et al., 1996; Turchi and Sarter, 1997). In addition, stimulation of α4β2 nicotinic receptors in the medial prefrontal cortex enhances performance in a visual attention task (Howe et al., 2010), while genetic deletion of these receptors in the mPFC impairs visual attention (Guillem et al., 2011) and auditory discrimination (Horst et al., 2012). Notably, transient rises in prefrontal ACh are significantly correlated with cue detection, suggesting that the temporal dynamics of cholinergic signaling are also critical for normal behavior (Parikh et al., 2007b). In primates, locally applied ACh enhances the attentional modulation of neuronal activity in the primary visual cortex, while the muscarinic antagonist scopolamine reduces the effects of attention (Herrero et al., 2008). Taken together, these findings suggest that cholinergic actions across both ionotropic and metabotropic receptors and diverse brain areas contribute to cognitive processing.
