Select properties of supramammillary input to adult-born dentate gyrus neurons

The hypothalamic supramammillary nucleus (SUM) projects to the hippocampal dentate gyrus (DG), a brain area crucial for learning, memory, and adult neurogenesis. How SUM inputs regulate adult-born DG (abDG) neurons to support memory processing remains unclear. Here, using monosynaptic tracing in adult mice, we identified a distinct subpopulation of abDG-targeting SUM neurons defined by large somata and low firing rate. Electrophysiological recordings revealed that these SUM neurons co-release glutamate and GABA onto abDGs, and that voluntary running selectively enhances GABAergic transmission. Chemogenetic silencing of SUM-DG GABAergic projections impaired pattern separation, the ability to make fine distinctions between similar stimuli, but not fear conditioning and spatial navigation memory. Altogether, our findings reveal that a distinct SUM subpopulation provides inhibitory modulation to abDG neurons, establishing a novel circuit mechanism for sparse encoding during pattern separation.