Cholinergic double duty: cue detection and attentional control

Abstract

Cholinergic signaling in the cortex involves fast or transient signaling as well as a relatively slower neuromodulatory component. These two components of cholinergic activity mediate separate yet interacting aspects of cue detection and attentional control. The transient component appears to support the activation of cue-associated task or response sets, whereas the slower modulatory component stabilizes task-set and context representations, therefore potentially facilitating top-down control. Evidence from humans expressing genetic variants of the choline transporter as well as from patients with degenerating cholinergic systems supports the hypothesis that attentional control capacities depend on levels of cholinergic neuromodulation. Deficits in cholinergic-attentional control impact diverse cognitive functions, including timing, working memory, and complex movement control.

Figure 1

Sustained Attention Task (SAT) performance, including the distractor version of this task (dSAT) of mice (left), rats (middle), and humans (right; some major task parameters are indicated below the individual task versions). The SAT consists of a semi-random sequence of signal and non-signal (or blank) trials. The intertrial interval (ITI) in all versions is variable, reducing the ability to time event onset. Following a signal or a non-signal event, a response window is opened either by extending two specialized nose-poke devices in the mouse version [‘MICARPs”; see 59], two retractable levers in the rat version [60], or by a low frequency buzz that activates to response keys on a computer keyboard in the human version [for details about signal presentation parameters see 3]. Subjects need to report a response in each trial within a defined period; a failure to do so is counted as an error of omission. Possible responses are hits (one response port or key) or misses (opposite response port or key) following signal events, or correct rejections or false alarms following non-signal events (reversed response port or key assignment.) A test session consists of 100–200 trials that are blocked post hoc (usually by time) to determine potential performance decrements. Hits and correct rejections are rewarded (water or pellets in rodents; symbol for later monetary reward in humans). Misses and false alarms have no further scheduled consequences and trigger, similar to hits and correct rejection responses, the next ITI. False alarms are relatively rare in all three species, and hits vary with signal duration. The ordinates in Fig. 1 depict the SAT score which combines the relative number of hits and correct rejections into one score that ranges from 0 (random response selection) to 1 (all responses are hits and correct rejections). Averaged over all signal durations, SAT scores (no distractor, black lines) generally are flat across sessions, with humans obviously performing robustly better than rodents. During dSAT sessions, the distractor, or perhaps more accurately the disruptor [this issue is discussed in 32], is turned on typically during trial blocks 2 and 3. In rodents, the distractor consists of the operant chamber houselight flashing on/off at 0.5 Hz. In humans, the screen alternates between silver and black at 10 Hz. As illustrated in Figure 1, the distractor suppresses performance in all three species, with rodents reaching chance level, followed by a relatively quick recovery of performance in block 4 and 5. In the presence of the distractor, humans adopt a more conservative and rodents a more liberal response bias [3], possibly also reflecting the qualitatively different capacity for top-down control in humans versus rodents. Our collective evidence indicates that cholinergic transients are necessary and sufficient to mediate hits, specifically in shift-hit trials. During the distractor, elevated levels of cholinergic neuromodulation predict the degree of post-distractor performance recovery and therefore is thought to mediate levels of topdown control designed to stabilize and recovery task performance (see main text).