A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Contextual encoding in the dorsal hippocampus (DHPC) may recruit hypothalamic feeding modules to calibrate eating across environments, but the mechanistic instantiation of cells and circuits that undergird these processes is limited. Single-cell transcriptomics and transsynaptic tracing of the dorsolateral septum (DLS) identified an evolutionarily conserved prodynorphin (Pdyn)-expressing subpopulation of somatostatin (Sst)-expressing inhibitory neurons that receives dense dorsal, but not ventral, hippocampal inputs. Circuit optogenetics, electrophysiology, and in vivo calcium imaging demonstrated that DLS(Pdyn) neurons inhibit GABAergic neurons of the lateral hypothalamic area (LHA), exhibit context-dependent neural responses to food rewards and aversive stimuli, and confer contextual and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS impaired context-dependent food reward consumption, suggesting a role for dynorphin/kappa opioid receptor signaling in these processes. Together, our findings highlight how ancient LHA feeding circuits integrate DHPC input through DLS(Pdyn) inhibitory neurons to link context with regulation of food consumption.