Cortical cholinergic signaling controls the detection of cues

The cortical cholinergic input system has been described as a neuromodulator system that influences broadly defined behavioral and brain states. The discovery of phasic, trial-based increases in extracellular choline (transients), resulting from the hydrolysis of newly released acetylcholine (ACh), in the cortex of animals reporting the presence of cues suggests that ACh may have a more specialized role in cognitive processes. Here we expressed channelrhodopsin or halorhodopsin in basal forebrain cholinergic neurons of mice with optic fibers directed into this region and prefrontal cortex. Cholinergic transients, evoked in accordance with photostimulation parameters determined in vivo, were generated in mice performing a task necessitating the reporting of cue and noncue events. Generating cholinergic transients in conjunction with cues enhanced cue detection rates. Moreover, generating transients in noncued trials, where cholinergic transients normally are not observed, increased the number of invalid claims for cues. Enhancing hits and generating false alarms both scaled with stimulation intensity. Suppression of endogenous cholinergic activity during cued trials reduced hit rates. Cholinergic transients may be essential for synchronizing cortical neuronal output driven by salient cues and executing cue-guided responses.Virtually all cortical regions and layers receive inputs from cholinergic neurons originating in the nucleus basalis of Meynert, the substantia innominata, and the diagonal band of the basal forebrain (BF). Reflecting the seemingly diffuse organization of this projection system, functional conceptualizations traditionally have described acetylcholine (ACh) as a neuromodulator that influences broadly defined behavioral and cognitive processes such as wakefulness, arousal, and gating of input processing (1, 2). However, anatomical studies have revealed a topographic organization of BF cholinergic cell bodies with highly segregated cortical projection patterns (3–7). Such an anatomical organization favors hypotheses describing the cholinergic mediation of discrete cognitive-behavioral processes. Studies assessing the behavioral effects of cholinergic lesions, recording from or stimulating BF neurons in behaving animals have supported such hypotheses, proposing that cholinergic activity enhances sensory coding and mediates the ability of reward-predicting stimuli to control behavior (8–17).In separate experiments using two different tasks, we reported the presence of phasic cholinergic release events (transients) in the medial prefrontal cortex (mPFC) of rodents trained to report the presence of cues (18, 19). These studies used choline-sensitive microelectrodes to measure changes in extracellular choline concentrations that reflect the hydrolysis of newly released ACh by endogenous acetylcholinesterase (SI Results and Discussion). Importantly, such cholinergic transients were not observed in trials in which cues were missed and in which the absence of a cue was correctly reported and rewarded. Cholinergic transients have thus been hypothesized to mediate the detection of cues, specifically defined as the cognitive process that generates a behavioral response by which subjects report the presence of a cue (20).Here we used optogenetic methods to test the causal role of cortical cholinergic transients in cue detection (as defined above). We used a task that consisted of cued and noncued trials and rewarded correct responses for both trial types (hits and correct rejections). Incorrect responses (misses and false alarms, respectively) were not rewarded. We hypothesized that hit rates would be enhanced by generating transients in conjunction with cues, and that hit rates will be reduced by silencing cue-associated endogenous cholinergic signaling. We further reasoned that if cholinergic transients are a mediator of the cue detection response, generating such transients on noncued trials could force invalid detections (false alarms).Phasic cholinergic activity was generated or silenced, in separate sessions, by photoactivation directed toward the cholinergic cell bodies of the BF or the cholinergic terminals locally in the right mPFC. The decision to target right mPFC was based on findings indicating that performance of the task used here enhances cholinergic function in the right, but not left, mPFC in mice (21) and activates right prefrontal regions in humans (19, 22). The present results support the hypothesis that the ability of cues to guide behavior is mediated by phasic cholinergic signaling. Particularly strong support for this hypothesis was obtained by the demonstration that, in the absence of cues, and thus of endogenous transients, photostimulation of either cholinergic soma in the BF or cholinergic terminals in the mPFC increased the number of invalid reports of cues (or false alarms).