Anna Schroeder: Inhibitory top-down projections from zona incerta control neocortical memory

Top-down projections convey a family of signals encoding previous experiences and current aims to sensory neocortex, where they converge with bottom-up information from the environment to enable perception and memory. Whereas top-down control has been attributed to excitatory pathways, the existence, connectivity and information content of inhibitory top-down projections remains elusive. Here we combine synaptic 2-photon calcium imaging, circuit mapping, cortex-dependent learning and chemogenetics to identify GABAergic afferents from the subthalamic zona incerta as a major source of top-down input to neocortex. Incertocortical transmission undergoes robust plasticity during learning that improves information transfer and controls behavioral memory. Unlike excitatory pathways, incertocortical afferents form a disinhibitory circuit which encodes learned top-down relevance in a bidirectional manner where the rapid appearance of negative responses serves as the main driver of changes in stimulus representation. Our results therefore reveal the distinctive contribution of long-range (dis)inhibitory afferents to the computational flexibility of neocortical circuits.