Dorsal raphe serotonergic neurons suppress feeding through redundant forebrain circuits

Serotonin (5HT) is a well-known anorexigenic molecule, and 5HT neurons of dorsal raphe nucleus (DRN) have been implicated in suppression of feeding; however, the downstream circuitry is poorly understood. Here we explored major projections of DRN^5HT neurons for their capacity to modulate feeding.

We used optogenetics to selectively activate DRN^5HT axonal projections in hypothalamic and extrahypothalamic areas and monitored food intake. We next used fiber photometry to image the activity dynamics of DRN^5HT axons and 5HT levels in projection areas in response feeding and metabolic hormones. Finally, we used electrophysiology to determine how DRN^5HT axons affect downstream neuron activity.

We found that selective activation of DRN^5HT axons in (DRN^5HT → LH) and (DRN^5HT → BNST) suppresses feeding whereas activating medial hypothalamic projections has no effect. Using in vivo imaging, we found that food access and satiety hormones activate DRN^5HT projections to LH where they also rapidly increase extracellular 5HT levels. Optogenetic mapping revealed that DRN^5HT → LH^vGAT and DRN^5HT → LH^vGlut2 connections are primarily inhibitory and excitatory respectively. Further, in addition to its direct action on LH neurons, we found that 5HT suppresses GABA release from presynaptic terminals arriving from AgRP neurons.

These findings define functionally redundant forebrain circuits through which DRN^5HT neurons suppress feeding and reveal that these projections can be modulated by metabolic hormones.