Endogenous opioid dynamics in the dorsal striatum sculpt neural activity to promote goal-directed action.

Endogenous neuropeptides are uniquely poised to regulate neuronal activity and behavior across multiple timescales. Traditional studies ascribing neuropeptide contributions to behavior lack spatiotemporal precision. The endogenous opioid dynorphin is a neuropeptide highly enriched in the dorsal striatum, a region critical for goal-directed behavior. However, the functional role of endogenous dynorphin- kappa opioid receptor (KOR) signaling in goal-directed behavior is unknown. Here, we report that local, time-locked dynorphin release from dorsomedial striatum medium spiny neurons (MSNs) is necessary and sufficient for goal-directed behavior using a suite of modern approaches, including conditional deletions, neuropeptide biosensor detection, two-photon imaging, and time-locked optogenetic manipulations of neuropeptide release. We discovered that glutamatergic axon terminals from the basolateral amygdala evoke striatal dynorphin release, resulting in feed-forward retrograde presynaptic G protein-coupled receptor (GPCR) inhibition to promote behavior. Collectively, our findings isolate a causal role for endogenous neuropeptide release at rapid timescales and subsequent pre-synaptic Gi-GPCR activity for promoting goal-directed behavior.