Hippocampal long-range GABAergic neurons target hippocampal-projecting cells of the supramammillary area

The supramammillary area (SuM) is well known for its direct connections to, and varied impacts on, the hippocampus. In contrast, relatively little is known about connectivity in the reverse direction - that is, the hippocampal influence on the SuM. We find that the hippocampus provides direct GABAergic inputs to the SuM, arising from multiple hippocampal subregions across dorsal and ventral hippocampus. Although both nitric oxide synthase-expressing long-range inhibitory NOS⁺ cells (LINCs) of the hippocampus and somatostatin-expressing subpopulations contribute to hippocampal-SuM communication, hippocampal cells projecting to the SuM do not express markers common to other subsets of hippocampal inhibitory projection neurons, including muscarinic cholinergic receptor 2 (M2R) or vasoactive intestinal protein (VIP). Viral tracing and optogenetic experiments indicate that hippocampal inhibitory cells densely target the lateral SuM and preferentially innervate SuM neurons that project back to the hippocampus. Notably this is not simple feedback inhibition, as there is cross-talk between circuits - dorsal hippocampal cells inhibit not only SuM cells projecting to dorsal hippocampus but also those projecting to the ventral hippocampus, and the same is true of ventral hippocampal cells. Collectively this work establishes that hippocampal-SuM circuitry is bidirectional and, in doing so, uncovers an additional role for hippocampal long-range GABAergic neurons in interregional communication. KEY POINTS: The supramammillary area (SuM) is a region of the hypothalamus with well-established impacts on memory and oscillations via direct projections to the hippocampus. In comparison, little is known about hippocampal influence over the SuM. Hippocampal-to-SuM direct communication is mediated by hippocampal inhibitory neurons, including long-range inhibitory NOS⁺ cells (LINCs) and somatostatin-expressing cells. Hippocampal inhibitory neurons projecting to the SuM originate from across hippocampal subregions (hilus, CA3, CA2 and CA1) and from across the hippocampal dorsal-ventral axis. Hippocampal inhibitory neurons preferentially target SuM neurons which project back to the hippocampus, establishing that hippocampal-SuM circuitry is bidirectional.