Endocannabinoid modulation of a reciprocal fronto-coerulear connection in contextual discrimination

The prefrontal cortex (PFC) and locus coeruleus (LC) form a bidirectional circuit essential for cognitive control and arousal. LC-derived norepinephrine (NE) influences PFC network dynamics, yet the mechanisms by which descending PFC inputs regulate LC activity and gate its neuromodulatory feedback remain unclear. Here, we describe an anatomical and functional PFC-LC loop subject to endocannabinoid (eCB) negative feedback. Optogenetic activation of PFC terminals in the LC enhances NE release and recruits NE-sensitive neuronal activity in the PFC. Under behaviorally relevant patterns of activation, LC-derived eCBs are mobilized, thereby weakening PFC-to-LC synaptic transmission. This limits subsequent NE release in the PFC and constrains the recruitment of NE-sensitive PFC neuronal assemblies. Modulation of this PFC-LC interaction shapes outcome discrimination in place conditioning tasks. By elucidating how eCB signaling modulates the PFC-LC loop, our findings reveal how these lipid molecules fine-tune NE signaling in the PFC, which is involved in cognitive and arousal-related processes.