Long-range GABAergic projections contribute to cortical feedback control of sensory processing.

In sensory systems, cortical areas send excitatory projections back to subcortical areas to dynamically adjust sensory processing. Here, we uncover for the first time the existence of a cortical inhibitory feedback to subcortical sensory areas. Investigating the olfactory system, we reveal that a subpopulation of GABAergic neurons in the anterior olfactory cortex target the olfactory bulb. Analogous inhibitory cortico-thalamic projections were also present in the somatosensory system. Long-range inhibitory inputs synapsed with both local and output neurons of the olfactory bulb. At the functional level, optogenetic activation of cortical GABAergic projections caused a net subtractive inhibition of both spontaneous and odor-evoked activity in local as well as output projection neurons, mitral and tufted cells. In tufted cells, but not mitral cells, this resulted in an enhanced separation of population odor responses. Furthermore, GABAergic corticofugal projections entrained network oscillations in the communication band between the cortex and the olfactory bulb. Targeted pharmacogenetic silencing of the cortical GABAergic outputs in the olfactory bulb impaired discrimination of similar odor mixtures. Thus, cortical GABAergic feedback represents a new circuit motif in sensory systems involved in refining sensory processing and perception.