Cortical cholinergic signaling controls the detection of cues

Abstract

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.V irtually 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. Cho...

What do phasic cholinergic signals do?

“…This finding indicates the necessity of cholinergic activity for signal detection but it does not identify the essential component of cholinergic neurotransmission (neuromodulatory or transient). Halorhodopsin photoactivationinduced silencing of cholinergic activity specifically during signal presentation reproduced the effects of cholinergic lesions (Gritton et al, 2016). This suggests that the primary cause of signal detection impairments in lesioned animals was the absence of cholinergic transients.…”

“…To test this possibility, we expressed channelrhodopsin (ChR2) in cholinergic neurons of (ChAT-Cre) mice and photostimulated these neurons at the level of the soma in the BF as well as the cholinergic terminals in the mPFC in SAT performing mice. Specifically, photostimulation coincided with signal or non-signal onset (for details see Gritton et al, 2016). …”

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

“…Using diverse research approaches ranging from assessing effects of selective lesions, amperometric measures of the fast, phasic, or transient component of cholinergic neurotransmission, microdialysis measures of levels of cholinergic neuromodulation, neurophysiological recordings, and optogenetic generation and attenuation of fast cholinergic transients in performing rodents, the basal forebrain cholinergic projection system to the cortex has been shown to mediate, necessarily, the incorporation of cues into cortical circuitry, thereby allowing such cues to control behavior (Avery, Dutt, & Krichmar, 2014; Goard & Dan, 2009; Gritton et al, 2016; Howe et al, 2013; Howe et al, 2017; McGaughy et al, 1996; Parikh, Kozak, Martinez, & Sarter, 2007; Pinto et al, 2013; Runfeldt, Sadovsky, & MacLean, 2014; Sarter, Howe, & Gritton, 2015; Sarter, Lustig, Berry, et al, 2016; Sarter, Lustig, Howe, Gritton, & Berry, 2014). Furthermore, levels of cholinergic neuromodulation influence the likelihood and the amplitudes of cholinergic transients that cause the detection of cues in attentional contexts (for a circuitry model underlying this interaction see Hasselmo & Sarter, 2011).…”

The Input-Output Relationship of the Cholinergic Basal Forebrain

“…ACh is released in the cortex by neurons whose cell bodies are located in the BF. Each of these cholinergic neurons supplies a small portion of cortex (Price and Stern, 1983), and ACh release is controlled precisely across different cortical regions and time scales, thought to be responsible for the variety of its cognitive effects (for review see Gritton et al, 2016; Muñoz and Rudy, 2014). However, the mechanism behind this control is unknown.…”