Synaptic inhibition in the lateral habenula shapes reward anticipation

Abstract

The lateral habenula (LHb) supports learning processes enabling the prediction of upcoming rewards. While reward-related stimuli decrease the activity of LHb neurons, whether this anchors on synaptic inhibition to guide reward-driven behaviors remains poorly understood. Here, we combine in vivo two-photon calcium imaging with Pavlovian conditioning in mice and report that anticipatory licking emerges along with decreases in cue-evoked calcium signals in individual LHb neurons. In vivo multiunit recordings and pharmacology reveal that the cue-evoked reduction in LHb neuronal firing relies on GABA_A-receptor activation. In parallel, we observe a postsynaptic potentiation of GABA_A-receptor-mediated inhibition, but not excitation, onto LHb neurons together with the establishment of anticipatory licking. Finally, strengthening or weakening postsynaptic inhibition with optogenetics and GABA_A-receptor manipulations enhances or reduces anticipatory licking, respectively. Hence, synaptic inhibition in the LHb shapes reward anticipation.

Keywords: GABA(A) receptors; cue-reward associative behavior; lateral habenula; synaptic inhibition; synaptic plasticity.