Orbitofrontal cortex drives predictive filtering of sensory responses.

Habituation is a crucial sensory filtering mechanism whose dysregulation can lead to a continuously intense world in disorders with hypersensitivity. Although habituation is often termed the simplest form of learning, its circuit mechanisms remain elusive. Conventional peripheral explanations fail to fully account for long-term habituation in complex sensory environments, leading to theories proposing top-down regulation. Here we evaluated two competing top-down mechanistic explanations for habituation in mice (growth in predictive filtering and waning of novelty-driven amplification) and identified an unexpected role for the orbitofrontal cortex (OFC) in predictive filtering. After daily sound exposure, neural habituation in the primary auditory cortex (A1) was reversed by inactivating the OFC. Top-down projections from the OFC, but not other frontal areas, carried predictive signals that grew with daily sound experience and suppressed A1 via somatostatin-expressing inhibitory neurons. Thus, prediction signals from the OFC cancel out anticipated stimuli by generating their 'negative images' in sensory cortices.