A brainstem circuit amplifies aversion

Abstract

Dynamic gain control of aversive signals enables adaptive behavioral responses. Although the role of amygdalar circuits in aversive processing is well established, the neural pathway for amplifying aversion remains elusive. Here, we show that the brainstem circuit linking the interpeduncular nucleus (IPN) with the nucleus incertus (NI) amplifies aversion and promotes avoidant behaviors. IPN GABA neurons are activated by aversive stimuli and their predicting cues, with their response intensity closely tracking aversive values. Activating these neurons does not trigger aversive behavior on its own but rather amplifies responses to aversive stimuli, whereas their ablation or inhibition suppresses such responses. Detailed circuit dissection revealed anatomically distinct subgroups within the IPN GABA neuron population, highlighting the NI-projecting subgroup as the modulator of aversiveness related to fear and opioid withdrawal. These findings unveil the IPN-NI circuit as an aversion amplifier and suggest potential targets for interventions against affective disorders and opioid relapse.

Keywords: addiction; chemogenetics; fear; fiber photometry; interpeduncular nucleus; learning and memory; medial habenula; nucleus incertus; opioids; single-cell reconstruction.