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GABAergic neurons in the laterodorsal tegmental nucleus (LDTGABA) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDTGABA neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDTGABA cell populations. Somatostatin-expressing (Sst+) LDTGABA neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDTGABA neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.
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•LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice•Sst+ LDTGABA interneurons encode reward by indirect disinhibition of mesolimbic DA system•VTA-projecting LDTGABA neurons promote aversion by directly inhibiting VTA DA neurons•VTA-projecting LDTGABA neurons selectively express Reelin
Du et al. reveal that two separate populations of LDTGABA neurons are involved in the regulation of distinct behavioral reactions to unpleasant stimuli. Long-range VTA-projecting (Reelin+) LDTGABA neurons directly relay aversive stimuli to the mesolimbic DA system. Sst-expressing LDTGABA interneurons conversely regulate the mesolimbic DA system through hypothalamic circuitry.