Prefrontal cholinergic transients mediating signal detection and attentional processing mode shifts. (a) Employing a cued appetitive response task, animals were trained to detect a rarely occurring cue that predicted reward delivery at one out of two reward ports (for details see [77]). Cue detection (as defined in the main text; [65]) was indicated by disengagement from ongoing behavior (typically grooming), orientation to and monitoring of the reward ports (see “detected cue”). As shown in (b) cues that were detected produced transient increases in cholinergic activity. No such transients were found in trials in which cues were missed. Importantly, reward was also delivered in such trials and thus animals eventually shifted from grooming behavior to port approach and reward retrieval. However, this was not associated with a cholinergic transient (for additional evidence and the effects of removal of prefrontal cholinergic inputs see [77]). (c) Main events of the sustained attention task (SAT). The task consists of a random sequence of signal and non-signal trials. Two seconds following an event the levers are extended, prompting the animal to report the presence or absence of a signal. Depending on the trial type, responses are classified as hits or misses and correct rejections or false alarms, respectively (see the color-coded response arrows in the outcome matrix). (d) Currents indicating ACh release in the prefrontal cortex during signal trials that yielded a hit (arrows indicate the time of signal presentation, lever extension, and correct lever press). Cholinergic transients were evoked by signals if the prior trial was a factual non-signal trial or a perceived non-signal trial (that is, a signal trial yielding a miss), but not if the prior trial also ended with a hit. Signals that resulted in misses never evoked transients, irrespective of the prior trial type (not shown; [78]) Collectively, these results indicate that prefrontal cholinergic transients mediate the shift from intrinsic or default-mode state-based activity to a state fostering signal detection. (a and b were reprinted from Neuron, Vol. 56, Parikh, V., Kozak, R., Martinez, V., Sarter, M., Prefrontal acetylcholine release controls cue detection on multiple time scales, p. 143 and 144. Copyright (2007) with permission from Elsevier.

Cholinergic transients evoked by local, prefrontal application (pressure ejections) of nicotine and the α4β2* nAChR agonist ABT-089. (a, b) Self-referenced traces depicting cholinergic transients produced by two pressure ejections (see arrows on the abscissa for timepoints) of nicotine or ABT-089. Compared with the transients evoked by nicotine, ABT-089 was more potent with respect to the amplitudes of the cholinergic transients (c). Furthermore, decay rates of cholinergic transients produced by nicotine were strikingly higher and dose-dependent when compared with ABT-089 (for additional, mechanistic data see [100]). The “sharper” and larger signals of α4β2* nAChR agonists are hypothesized to underlie the more robust beneficial attentional effects of these compounds. (Reprinted from the Journal of Neuroscience, Parikh et al. 2008, with permission of the Journal of Neuroscience/Society for Neuroscience).

Model describing the main components of the prefrontal cortex (PFC) circuitry mediating signal detection and processing mode up-shifts. The model combines well-documented evidence with parsimonious assumptions required to explain our electrochemical and performance data (see main text for details). The glutamatergic (GLU) inputs to the PFC, originating from the mediodorsal thalamic nucleus (MD) “import” a preattentionally processed representation of the signal into the PFC. MD neurons are part of a network that includes the thalamic reticular nucleus (TRN) and its topographic afferents from sensory cortical regions, and has been proposed to generate a signal-associated “attentional searchlight”, a term that refers to a pre-attentional narrowing of the “place demanding attention”. The signal-evoked glutamatergic transient in the cortex generates a cholinergic transient, via stimulation of ionotropic presynaptic glutamate receptors [100]. The cholinergic transient mediates the actual detection process or, depending on the task, a processing mode shift that fosters detection [77,78]. Prefrontal output neurons are presumed to be stimulated by ACh primarily via muscarinic (m)AChRs [129], thereby organizing the behavioral responses that indicate successful detection. The terminals of the MD inputs to the PFC are equipped with α4β2* nAChRs and nAChR agonists enhance detection performance and processing mode shifts primarily by positively modulating GLU release and thereby augmenting the amplitudes of the cholinergic transients that are essential for detection. While this glutamatergic-cholinergic interaction is sufficient to explain the presence of signal salience-dependent hit rates, it does not account for occasional misses of salient stimuli or the acute, detrimental effects of distractors and subsequent performance recovery. We speculate that as a result of, for example, task-unrelated increases in activity of this network prior to the presentation of signals, detection interference results from GABAergic inhibition of cholinergic terminals [105]. The cholinergic receptors situated on GABAergic interneurons are not clear but likely involve *β2* subunit containing nAChRs and also mAChRs [130,131]. These interneurons are also innervated by other cortical neurons (as symbolized by the connection from the neurons on top of the figure) and thus potentially allow increases in activity of the default-mode network to inhibit cholinergic terminals [132].

Effects of systemic administration of nicotine on the detection of cues in a cued appetitive response task and on cholinergic transients mediating cue detection [77,133]. The figure shows self-referenced traces indicating acetylcholine release in animals performing a cued appetitive response task (see Figure 1a), during trials involving cue detection (upper pair) and in which the cue was missed (lower pair). Administration of 0.4 mg/kg nicotine augmented the amplitude of detected cue-evoked cholinergic transients and also slowed the decay rate of these transients. Nicotine did not affect the flat traces recored during trials with missed cues. Nicotine increased the number of trials in which the cue was detected (see Figure 1) by 33%. Furthermore, the latency from cue detection to reward retrieval was reduced from 3.4±0.75 s (saline) to 2.4±0.8 s (nicotine).