Howard J. Gritton

Deterministic functions of cortical acetylcholine

Traditional descriptions of the basal forebrain cholinergic projection system to the cortex have focused on neuromodulatory influences, that is, mechanisms that modulate cortical information processing but are not necessary for mediating discrete behavioral responses and cognitive operations. This review summarises and conceptualises the evidence in support of more deterministic contributions of cholinergic projections to cortical information processing. Through presynaptic receptors expressed on cholinergic terminals, thalamocortical and corticocortical projections can evoke brief cholinergic release events. These acetylcholine (ACh) release events occur on a fast, sub‐second to seconds‐long time scale (‘transients’). In rats performing a task requiring the detection of cues as well as the report of non‐cue events cholinergic transients mediate the detection of cues specifically in trials that involve a shift from a state of monitoring for cues to cue‐directed responding. Accordingly, ill‐timed cholinergic transients, generated using optogenetic methods, force false detections in trials without cues. We propose that the evidence is consistent with the hypothesis that cholinergic transients reduce detection uncertainty in such trials. Furthermore, the evidence on the functions of the neuromodulatory component of cholinergic neurotransmission suggests that higher levels of neuromodulation favor staying‐on‐task over alternative action. In other terms, higher cholinergic neuromodulation reduces opportunity costs. Evidence indicating a similar integration of other ascending projection systems, including noradrenergic and serotonergic systems, into cortical circuitry remains sparse, largely because of the limited information about local presynaptic regulation and the limitations of current techniques in measuring fast and transient neurotransmitter release events in these systems.

Cortical cholinergic signaling controls the detection of cues

Significance Virtually the entire cortex is innervated by cholinergic projections from the basal forebrain. Traditionally, this neuronal system has been described as a neuromodulator system that supports global states such as cortical arousal. The presence of fast and regionally specific bursts in cholinergic neurotransmission suggests a more specialized role in cortical processing. Here we used optogenetic methods to investigate the capacity of phasic cholinergic signaling to control behavior. Our findings indicate a causal role of phasic cholinergic signaling in using external cues to guide behavioral choice. These findings indicate the significance of phasic cholinergic activity and also illustrate the potential impact of abnormal, phasic cholinergic neurotransmission on fundamental cognitive functions that involve cue-based behavioral decisions. 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.

Antidepressant Suppression of Non-REM Sleep Spindles and REM Sleep Impairs Hippocampus-Dependent Learning While Augmenting Striatum-Dependent Learning

Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T-maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State–performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS.

Cognitive Performance as a Zeitgeber: Cognitive Oscillators and Cholinergic Modulation of the SCN Entrain Circadian Rhythms

The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals that can synchronize or entrain to environmental cues. Although light exerts powerful influences on SCN output, other non-photic stimuli can modulate the SCN as well. We recently demonstrated that daily performance of a cognitive task requiring sustained periods of attentional effort that relies upon basal forebrain (BF) cholinergic activity dramatically alters circadian rhythms in rats. In particular, normally nocturnal rats adopt a robust diurnal activity pattern that persists for several days in the absence of cognitive training. Although anatomical and pharmacological data from non-performing animals support a relationship between cholinergic signaling and circadian rhythms, little is known about how endogenous cholinergic signaling influences SCN function in behaving animals. Here we report that BF cholinergic projections to the SCN provide the principal signal allowing for the expression of cognitive entrainment in light-phase trained animals. We also reveal that oscillator(s) outside of the SCN drive cognitive entrainment as daily timed cognitive training robustly entrains SCN-lesioned arrhythmic animals. Ablation of the SCN, however, resulted in significant impairments in task acquisition, indicating that SCN-mediated timekeeping benefits new learning and cognitive performance. Taken together, we conclude that cognition entrains non-photic oscillators, and cholinergic signaling to the SCN serves as a temporal timestamp attenuating SCN photic-driven rhythms, thereby permitting cognitive demands to modulate behavior.

Acetylcholine release in prefrontal cortex promotes gamma oscillations and theta–gamma coupling during cue detection

The capacity for using external cues to guide behavior (“cue detection”) constitutes an essential aspect of attention and goal-directed behavior. The cortical cholinergic input system, via phasic increases in prefrontal acetylcholine release, plays an essential role in attention by mediating such cue detection. However, the relationship between cholinergic signaling during cue detection and neural activity dynamics in prefrontal networks remains unclear. Here we combined subsecond measures of cholinergic signaling, neurophysiological recordings, and cholinergic receptor blockade to delineate the cholinergic contributions to prefrontal oscillations during cue detection in rats. We first confirmed that detected cues evoke phasic acetylcholine release. These cholinergic signals were coincident with increased neuronal synchrony across several frequency bands and the emergence of theta–gamma coupling. Muscarinic and nicotinic cholinergic receptors both contributed specifically to gamma synchrony evoked by detected cues, but the effects of blocking the two receptor subtypes were dissociable. Blocking nicotinic receptors primarily attenuated high-gamma oscillations occurring during the earliest phases of the cue detection process, while muscarinic (M1) receptor activity was preferentially involved in the transition from high to low gamma power that followed and corresponded to the mobilization of networks involved in cue-guided decision making. Detected cues also promoted coupling between gamma and theta oscillations, and both nicotinic and muscarinic receptor activity contributed to this process. These results indicate that acetylcholine release coordinates neural oscillations during the process of cue detection. SIGNIFICANCE STATEMENT The capacity of learned cues to direct attention and guide responding (“cue detection”) is a key component of goal-directed behavior. Rhythmic neural activity and increases in acetylcholine release in the prefrontal cortex contribute to this process; however, the relationship between these neuronal mechanisms is not well understood. Using a combination of in vivo neurochemistry, neurophysiology, and pharmacological methods, we demonstrate that cue-evoked acetylcholine release, through distinct actions at both nicotinic and muscarinic receptors, triggers a procession of neural oscillations that map onto the multiple stages of cue detection. Our data offer new insights into cholinergic function by revealing the temporally orchestrated changes in prefrontal network synchrony modulated by acetylcholine release during cue detection.