Dynorphin counteracts excitatory co-transmission in a lateral hypothalamus–locus coeruleus circuit underlying stress-induced anxiety

Anxiety disorders are highly prevalent, yet the circuit mechanisms linking stress to pathological anxiety remain incompletely understood. The locus coeruleus (LC), the brain’s primary noradrenaline source, receives dense innervation from the lateral hypothalamus (LH). Here, we investigate the LH prodynorphin→LC noradrenergic (LHdyn→LCNA) pathway in stress-induced anxiety. We find that restraint stress activates LHdyn neurons, which form monosynaptic connections onto LCNA neurons. In male mice, chemogenetic activation of this pathway promotes anxiety-like behavior—an effect attenuated by intra-LC orexin receptor blockade but exacerbated by kappa opioid receptor antagonism, indicating that co-released dynorphin acts as an intrinsic anxiolytic brake. Conversely, chemogenetic inhibition is anxiogenic in naïve male mice yet anxiolytic after chronic restraint stress. Using genetically encoded sensors, we show that dynorphin and glutamate are co-released in the LC, and that elevating dynorphin tone suppresses LCNA hyperactivity and reduces anxiety. These findings reveal a push–pull mechanism wherein excitatory transmission is intrinsically balanced by co-released dynorphin, offering a framework for understanding stress-related psychopathology. The locus coeruleus, the brain’s main source of noradrenaline, helps regulate stress responses. Here, authors show that dynorphin co-released from lateral hypothalamus neurons acts as an anxiolytic brake in the locus coeruleus, balancing excitatory signals to control stress-induced anxiety in mice.