Learning-dependent cholinergic plasticity reconfigures cortical circuit dynamics

Neuromodulation by acetylcholine (ACh) plays a critical role in reshaping neural dynamics in the neocortex as a function of development, behavioral state, and learning ^1–6 . Prior work suggests cholinergic signaling can act as a gate for the subsequent induction of circuit plasticity ^3,7,8 . However, modification of ACh release could also be a direct mechanism for the expression of cortical plasticity. Here, we combine widefield and 2-photon imaging in head-fixed mice to show that visual fear conditioning leads to a selective, cue-dependent release of ACh in primary visual cortex that enhances visually-evoked neuronal responses via excitation of layer 1 GABAergic interneurons and resulting disinhibition of local excitatory pyramidal neurons. Cholinergic signaling through muscarinic receptors in visual cortex is necessary for both the enhanced visual response and conditioned fear behavior. Our results demonstrate a novel capacity for conditioned release of ACh in sensory cortex to serve as a mechanism for sensory-guided behavioral learning. Rather than acting as a simple gate, cortical neuromodulation may thus play a central role in the expression of learned behavior.