The Locomoting State Selectively Amplifies Activity of Sensitizing Neurons in Primary Visual Cortex

Sensory processing in the cortex reflects both adaptation to external stimuli and changes in internal state. To investigate how these processes interact in layer 2/3 of mouse V1 we combined calcium imaging, optogenetics and circuit modelling. We find that locomotion preferentially increases the responses of pyramidal cells (PCs) that sensitize during visual stimulation compared to those that depress. A model explains this differential modulation through: (i) variations in the strength of PV and SST connectivity to individual PCs, (ii) broad locomotion-dependent weakening of PC and PV synapses, and (iii) reduced SST inhibition targeting sensitizing PCs. Differences in PV:SST input ratios across sensitizing and depressing PCs can be reproduced by a random-connectivity model based on measured interneuron densities, connection probabilities and synaptic strengths. Thus, stochastic variation in local inhibitory connectivity can explain much of the functional heterogeneity across PCs, while state-dependent modulation of inhibitory synapses reorganizes this balance during locomotion to bias cortical population activity towards sensitizing dynamics. The apparently paradoxical combination of increased PC response but decreased synaptic strength is consistent with a state-dependent gating mechanism that boosts signals leaving V1 while simultaneously preventing disruption of the local excitatory-inhibitory balance required for stable computation.