Reward-timing-dependent bidirectional modulation of cortical microcircuits during optical single-neuron operant conditioning

Animals rapidly adapt to environmental change. To reveal how cortical microcircuits are rapidly reorganized when an animal recognizes novel reward contingency, we conduct two-photon calcium imaging of layer 2/3 motor cortex neurons in mice and simultaneously reinforce the activity of a single cortical neuron with water delivery. Here we show that when the target neuron is not relevant to a pre-trained forelimb movement, the mouse increases the target neuron activity and the number of rewards delivered during 15-min operant conditioning without changing forelimb movement behaviour. The reinforcement bidirectionally modulates the activity of subsets of non-target neurons, independent of distance from the target neuron. The bidirectional modulation depends on the relative timing between the reward delivery and the neuronal activity, and is recreated by pairing reward delivery and photoactivation of a subset of neurons. Reward-timing-dependent bidirectional modulation may be one of the fundamental processes in microcircuit reorganization for rapid adaptation. The mammalian brain is able to rapidly adapt to environmental changes, but it is unclear how this occurs at the level of the single neuron. Hira et al. use two-photon calcium imaging of neurons in the mouse motor cortex after a lever-pull task to demonstrate rapid operant conditioning of single neurons.