Dynorphin modulates reward-seeking actions through a pallido-amygdala cholinergic circuit

The endogenous opioid peptide dynorphin and its receptor κ-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here, we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and reward-seeking behavior in mice. On one hand, dynorphin acts postsynaptically via KORs on VP GABAergic neurons to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to facilitate learning and invigorate actions. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulates behavior through the cholinergic system and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.