Top-down regulation of subcortical regions by hippocampal long-range inhibition

The hippocampus is essential for memory formation, and its outputs to other brain regions are mediated primarily by long-range glutamatergic projections from pyramidal neurons in the subiculum and CA1. By contrast, long-range γ-aminobutyric acid (GABAergic) inhibitory projections from the hippocampus to extrahippocampal regions are poorly understood. Here, we report that a population of somatostatin-expressing (SOM⁺) neurons in the dorsal hippocampus, including dual-projecting SOM⁺ neurons, can robustly regulate the medial septum (MS) and supramammillary nucleus (SuM)-two subcortical regions critical for generating theta oscillations. We find that the hippocampal SOM⁺ neurons send long-range projections to both MS and SuM, preferentially suppressing GABAergic and glutamatergic neurons in MS and fast-spiking neurons in SuM. Rhythmic stimulation of SOM⁺ terminals at theta frequencies robustly entrains firing of MS and SuM neurons at theta frequencies ex vivo and significantly enhances theta power in vivo. Taken together, our findings reveal a novel top-down long-range inhibitory pathway well positioned to coordinate hippocampal-subcortical rhythmic activity important for memory, such as theta rhythm.