Highlights d Chronic in vivo two-photon calcium imaging of >36k neurons in mouse auditory cortex d Drift of auditory representations despite stable environmental conditions d Increased co-activation of neurons by CS+ and nonCS+ sounds after conditioning d Degree of co-activation is predictive of behavioral generalization

Recent long-term measurements of neuronal activity have revealed that, despite stability in large-scale topographic maps, the tuning properties of individual cortical neurons can undergo substantial reformatting over days. To shed light on this apparent contradiction, we captured the sound response dynamics of auditory cortical neurons using repeated 2-photon calcium imaging in awake mice. We measured sound-evoked responses to a set of pure tone and complex sound stimuli in more than 20,000 auditory cortex neurons over several days. We found that a substantial fraction of neurons dropped in and out of the population response. We modeled these dynamics as a simple discrete-time Markov chain, capturing the continuous changes in responsiveness observed during stable behavioral and environmental conditions. Although only a minority of neurons were driven by the sound stimuli at a given time point, the model predicts that most cells would at least transiently become responsive within 100 days. We observe that, despite single-neuron volatility, the population-level representation of sound frequency was stably maintained, demonstrating the dynamic equilibrium underlying the tonotopic map. Our results show that sensory maps are maintained by shifting subpopulations of neurons “sharing” the job of creating a sensory representation.

Cortical function and the processing of sensory stimuli is remarkably robust against the continuous loss of neurons during aging, but also accelerated loss during prodromal stages of neurodegeneration. Population activity of neurons in sensory cortices builds a representation of the environment in form of a map that is structured in an informative way for guiding behavior. Here, we used the mouse auditory cortex as a model and probed the robustness of a representational map against the removal functionally characterized neurons. Specifically, we tested in how far the structure of the representational map is safeguarded by homeostatic network mechanisms. We combined longitudinal two-photon calcium imaging of population responses evoked by a diverse set of sound stimuli in the mouse auditory cortex with a targeted microablation of individual, functionally characterized neurons. Unilateral microablation of 30 - 40 selected sound-responsive layer 2/3 neurons led to a temporary collapse of the representational map that showed a subsequent recovery. At the level of individual neurons, we observed that the recovery was predominantly driven by neurons that were unresponsive to the sounds before microablation and gained responsiveness during the time course of several days. The remodeling of the spared network was mediated by a shift of the distribution of tuning curves towards the ablated neurons and was accompanied by a shift in the excitation/inhibition balance. Together, our findings provide a link between the plasticity of individual neurons and the population dynamics of sensory representations mediating robustness of cortical function. The dynamic reconstitution of the structure of activity patterns evoked by sensory stimuli despite a permanent loss of neurons in the network demonstrates a homeostatic maintenance of sensory representations in the neocortex.