Goodwin, D.; Boja, A.; Tessereau, C.; Li, G.; Li, Y.; Rule, M. E.; Brown, J. T.; Mellor, J. R.; Witton, J.

Accurate learning requires the brain to distinguish between expected and unexpected uncertainties so that new information can update memory appropriately. It is proposed that the neuromodulator acetylcholine reconfigures neuronal networks for learning and is a key factor signalling uncertainty. Here we tested this hypothesis by measuring acetylcholine release and neuronal representations in the retrosplenial cortex of mice whilst challenging them with expected and unexpected uncertainties of reward location. Acetylcholine release increased with changes in expected uncertainty but only responded to unexpected uncertainty coincident with contextual shifts that altered expected uncertainty. In tandem, as expected uncertainty increased, neuronal representations initially shifted from a position reference frame to focus on salient landmarks, such as reward location. Transitions in expected uncertainty also accelerated remapping of representations and behavioural adaptation when unexpected uncertainty was experienced. Thus, we demonstrate acetylcholine release discerns between types of uncertainty and positively correlates with learning speed in uncertain environments.