Cholinergic modulation of reinforcement learning and prefrontal value computations under uncertainty
Journal:
bioRxiv
Published Date:
May 8, 2026
Abstract
The neuromodulator acetylcholine has been suggested to govern learning under uncertainty. Here, we investigated the role of muscarinic acetylcholine receptors in reward-guided learning and decision making under different degrees of uncertainty. We administered the muscarinic antagonist biperiden (4 mg) to healthy male participants (n = 43) in a within-subjects, placebo-controlled design. Participants performed a gambling and a learning task involving different levels of uncertainty, while magnetoencephalography (MEG) was recorded. We show that biperiden did not affect decision making in the gambling task, where no learning was required. However, in the learning task, where option values were associated with uncertainty, biperiden reduced the sensitivity to probabilities, particularly when choice-outcome-contingencies switched frequently. Reinforcement learning models revealed that the change in behaviour was caused by noisier estimates of probabilities resulting from increased learning rates for rewarded choices under biperiden. These behavioural findings were paralleled by elimination of the lateral prefrontal representation of learnt reward probability in high-beta (20 - 30 Hz) power under biperiden. Together, these findings suggest that muscarinic acetylcholine transmission controls learning in highly uncertain contexts, when the demand for carefully calibrated adjustments is highest.
