Prefrontal Cholinergic Mechanisms Instigating Shifts from Monitoring for Cues to Cue-Guided Performance: Converging Electrochemical and fMRI Evidence from Rats and Humans

Abstract

We previously reported involvement of right prefrontal cholinergic activity in veridical signal detection. Here, we first recorded real-time acetylcholine release in prefrontal cortex during specific trial sequences in rats performing a task requiring signal detection as well as rejection of non-signal events. Cholinergic release events recorded with sub-second resolution (“transients”) were observed only during signal-hit trials, not during signal-miss trials or non-signal events. Moreover, cholinergic transients were not observed for consecutive hits; instead they were limited to signal-hit trials that were preceded by factual or perceived non-signal events (“incongruent hits”). This finding suggests that these transients mediate shifts from a state of perceptual attention, or monitoring for cues, to cue-evoked activation of response rules and the generation of a cue-directed response. Next, to determine the translational significance of the cognitive operations supporting incongruent hits we employed a version of the task previously validated for use in research in humans and BOLD-fMRI. Incongruent hits activated a region in the right rostral prefrontal cortex (BA 10). Furthermore, greater prefrontal activation was correlated with faster response times for incongruent hits. Finally, we measured tissue oxygen in rats, as a proxy for BOLD, and found prefrontal increases in oxygen levels solely during incongruent hits. These cross-species studies link a cholinergic response to a prefrontal BOLD activation and indicate that these interrelated mechanisms mediate the integration of external cues with internal representations to initiate and guide behavior.

Cortical cholinergic signaling controls the detection of cues

“…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.…”

“…In contrast to the robust effects of laser stimulation in ChR2 mice, in control animals expressing EYFP alone, neither stimulation at the level of BF cholinergic neurons nor at cholinergic terminals in the mPFC ( Photostimulation During Noncued Trials Enhances False Alarms. As a strong test of the hypothesis that cholinergic transients are causal in mediating cue detection, we tested whether generating transients on noncue trials, where transients do not occur (19), can force false alarms (Fig. 5).…”

“…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).…”

“…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).…”

Targeting α4β2 Nicotinic Acetylcholine Receptors in Central Nervous System Disorders: Perspectives on Positive Allosteric Modulation as a Therapeutic Approach

“…Within attention, a4b2 nAChRs have been proposed to modulate transient release of ACh and glutamate in the medial prefrontal cortex (mPFC) necessary for cue detection in a rat sustained-attention task [30]. An equivalent phenomenon of increased prefrontal neuronal activity upon stimulus presentation in a simple attention task has been observed in human beings [31]. Although the latter study does not address the involvement of a4b2 nAChRs, clinical trials investigating a4b2 agonists in disorders displaying attentional deficits, for example attention-deficit/hyperactivity disorder (ADHD), have shown promising results [32,33].…”