This same state would also have been engaged during the long inter-trial intervals in the task
described in Parikh et al. Inhibitor Library high throughput (2007). Importantly, parallel experiments employing functional MRI in human subjects revealed coincident basal forebrain and prefrontal activation during incongruent hits, as well as in prefrontal oxygen levels in rats (for details see Howe et al., 2013). Combined, these data support the presence a prefrontal cholinergic mechanism that is preserved across species and supports attentional performance by forcing shifts from monitoring to cue-directed attention. Evidence for the deterministic role of cholinergic transients in attentional performance was obtained from a subsequent set of studies that demonstrated that the generation or suppression of such transients, using optogenetic methods, enhances or reduces, respectively, hit rates in SAT-performing mice (H. Gritton, W.M. Howe & M. Sarter, unpublished observations). Specifically, if transients are evoked to coincide with cues, hit rates increase; this is most robustly demonstrated for trials in which cue illumination is briefest in duration. Correspondingly, if endogenously generated cholinergic transients are suppressed
using opsins that inhibit depolarisation, animals detect fewer cues. These data suggest that cholinergic transients promote a shift to cue-associated response representations. In what is perhaps an even more direct demonstration this website of the causal relationship between phasic cholinergic
signaling and cue ‘detection’, artificially generating a cholinergic transient on non-signal trials increases the likelihood Casein kinase 1 of a false alarm. These induced, ill-timed transients produce false alarms in as many as 50% of such trials (as opposed to < 10% at baseline). This finding supports the hypothesis that cholinergic transients increase the probability for a discrete behavioral response, the reporting of a signal. Generating transients in the absence of signals ‘inserts’ the cholinergic activity normally generated by a detected, incongruent cue. Thus, we hypothesise that cholinergic transients are a sufficient cause for incongruent hits. Clearly, this hypothesis requires more testing, including more stringent manipulations of cholinergic transient activity during controlled sequences of signal and nonsignal trials. The timecourse of cholinergic transients (Fig. 1B) leads to additional speculation about their function. Specifically, cholinergic activity extends beyond the completion of incongruent hits and persists into the subsequent inter-trial interval, peaking at ~ 6 s following the cue (see fig. 2 in Howe et al., 2013). This ongoing activity is not likely to be related to the mediation of the actual hit in that particular trial. Rather, such prolonged cholinergic activity may serve as a reporter that binds action selection with outcome.