Inhibitory top-down projections from zona incerta mediate neocortical memory

• Published in: Neuron (Cambridge, Mass.) Mass.), 2023-03, Vol.111 (5), p.727-738.e8
• Main Authors: Schroeder, Anna, Pardi, M. Belén, Keijser, Joram, Dalmay, Tamas, Groisman, Ayelén I., Schuman, Erin M., Sprekeler, Henning, Letzkus, Johannes J.
• Format: Article
• Language: English
• Subjects: Animals; associative memory; circuit tracing; disinhibition; layer 1; Learning - physiology; Life Sciences; long-range inhibition; Mice; Neocortex - physiology; neocortical circuits; plasticity; synaptic in vivo calcium imaging; top-down information; Zona Incerta
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.12.010

Top-down projections convey a family of signals encoding previous experiences and current aims to the sensory neocortex, where they converge with external bottom-up information 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 remain elusive. Here, we combine synaptic two-photon calcium imaging, circuit mapping, cortex-dependent learning, and chemogenetics in mice to identify GABAergic afferents from the subthalamic zona incerta as a major source of top-down input to the neocortex. Incertocortical transmission undergoes robust plasticity during learning that improves information transfer and mediates behavioral memory. Unlike excitatory pathways, incertocortical afferents form a disinhibitory circuit that 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. [Display omitted] •Zona incerta sends long-range inhibitory projections to auditory cortex layer 1•These axons transmit integrated top-down information that is essential for learning•Sensory stimulus encoding in incertocortical boutons is highly experience dependent•Learned top-down relevance is encoded in a bidirectional and balanced fashion Schroeder et al. identify a key pathway that flexibly tunes neocortical computations according to the individual’s experience. These long-range inhibitory afferents derive from the subthalamic zona incerta, preferentially target neocortical interneurons, and encode the learned top-down relevance of sensory information in a bidirectional and balanced fashion to enable memory.