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Cell. 2015 Aug 27;162(5):1155-68. doi: 10.1016/j.cell.2015.07.057.

Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback.

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Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1083, Hungary. Electronic address:
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:


Basal forebrain cholinergic neurons constitute a major neuromodulatory system implicated in normal cognition and neurodegenerative dementias. Cholinergic projections densely innervate neocortex, releasing acetylcholine to regulate arousal, attention, and learning. However, their precise behavioral function is poorly understood because identified cholinergic neurons have never been recorded during behavior. To determine which aspects of cognition their activity might support, we recorded cholinergic neurons using optogenetic identification in mice performing an auditory detection task requiring sustained attention. We found that a non-cholinergic basal forebrain population-but not cholinergic neurons-were correlated with trial-to-trial measures of attention. Surprisingly, cholinergic neurons responded to reward and punishment with unusual speed and precision (18 ± 3 ms). Cholinergic responses were scaled by the unexpectedness of reinforcement and were highly similar across neurons and two nuclei innervating distinct cortical areas. These results reveal that the cholinergic system broadcasts a rapid and precisely timed reinforcement signal, supporting fast cortical activation and plasticity.

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