The lateral habenula mediates the association of a conditioned stimulus with the absence of an appetitive unconditioned stimulus

The lateral habenula (LHb) has been implicated in conditioned inhibition. Here, the modulating effects of LHb activity on the association of a conditioned stimulus (CS) with the nonoccurrence of an unconditioned stimulus (US) were assessed in vivo using chemogenetic methods. Animals initially received explicitly unpaired CS light and US food presentations. Animals subjected to a retardation-of-acquisition task subsequently underwent light and food pairings, whereas those subjected to a summation task underwent compound light-tone and food pairings. The inhibitory light strength was assessed based on retardation of the acquisition of food-cup conditioned responses (CRs) in light-food pairings and comparisons of food-cup CRs to each stimulus in a CS-alone test following compound training. Neurotoxic LHb lesions and chemogenetic LHb inhibition throughout unpaired training attenuated the inhibitory light strength. Furthermore, chemogenetic LHb activation accelerated the decline in CR induced by repeated light-alone presentations following light-food pairings. Therefore, the LHb critically contributes to conditioned inhibition.