Basal forebrain-derived acetylcholine encodes valence-free reinforcement prediction error

Abstract

Acetylcholine (Ach) is released by the cholinergic basal forebrain (CBF) throughout the cortical mantle and is implicated in behavioral functions ranging from arousal to attention to learning. Yet what signal ACh provides to cortex remains unresolved, hindering our understanding of its functional roles. Here we demonstrate that the CBF signals unsigned reinforcement prediction error, in contrast to dopamine (DA) neurons that encode reward 25 prediction error. We show that both CBF neuronal activity and acetylcholine (ACh) release at cortical targets signal reinforcement delivery, acquire responses to predictive stimuli and show diminished responses to expected outcomes, hallmarks of a prediction error. To compare ACh with DA, we simultaneously monitored the activity of both neuromodulators during a serial reversal learning task. ACh tracked learning as swiftly as DA during acquisition but lagged 30 slightly during extinction, suggesting that these neuromodulators play complementary roles in reinforcement as their patterns of innervation, cellular targets, and signaling mechanisms are themselves complementary. Through retrograde viral tracing we show that the cholinergic and dopaminergic systems engage overlapping upstream circuits, accounting for their coordination during learning. This predictive and valence-free signal explains how ACh can proactively and 35 retroactively improve the processing of behaviorally important stimuli, be they good or bad.

Acetylcholine is released in the basolateral amygdala in response to predictors of reward and enhances the learning of cue-reward contingency

“…Plasticity related to learning has also been observed in cholinergic neurons in the basal forebrain complex during aversive trace conditioning, such that after several training days, neuronal activity spans the delay between CS and US ( Guo et al, 2019 ). Additionally, a recent study suggested that ACh may signal a valence-free reinforcement prediction error ( Sturgill et al, 2020 ). Future studies on the selective inputs to NBM to BLA cholinergic neurons would be of interest to identify the links between brain areas involved in prediction error coding.…”

“…Additionally, a recent study suggested that ACh may signal a valence-free reinforcement prediction error (Sturgill et al, 2020). Future studies on the selective inputs to NBM to BLA cholinergic neurons would be of interest to identify the links between brain areas involved in prediction error coding.…”

Cortical ChAT+ neurons co-transmit acetylcholine and GABA in a target- and brain-region-specific manner

“…Acetylcholine (ACh) is a neurotransmitter and neuromodulator that is released throughout the mammalian cortex at times of alertness and arousal ( Teles-Grilo Ruivo et al, 2017 ) in order to promote learning and memory ( Hasselmo, 2006 ), modulate sensory perception ( Pinto et al, 2013 ), gate plasticity ( Morishita et al, 2010 ; Rasmusson, 2000 ), and enhance the detection of salient sensory cues and reinforcement ( Parikh et al, 2007 ; Sarter et al, 2009 ; Sarter et al, 2014 ; Sturgill et al, 2020 ). Most cortical ACh originates from subcortical nuclei in the basal forebrain Mesulam, 1995 whose long-range axons innervate broad regions of cortex and release ACh to modulate cortical function over fast and slow time scales ( Sarter et al, 2009 ; Picciotto et al, 2012 ).…”

Cortical ChAT+neurons co-transmit acetylcholine and GABA in a target- and brain-region specific manner

“…Acetylcholine (ACh) is a neurotransmitter and neuromodulator that is released throughout the mammalian cortex at times of alertness and arousal 1 in order to promote learning and memory 2 , modulate sensory perception 3 , gate plasticity 4,5 , and enhance the detection of salient sensory cues and reinforcement 6–9 . Most cortical ACh originates from subcortical nuclei in the basal forebrain 10 whose long-range axons innervate broad regions of cortex and release ACh to modulate cortical function over fast and slow time scales 7,11 .…”