Inhibitory hippocampal projections to the Supramammillary area - PROJECT SUMMARY The supramammillary area (SuM) is increasingly appreciated for its role in a variety of functions, including spatial and social novelty processing via its connections with the hippocampus. Specifically, the SuM has projections to the CA2 and ventral dentate gyrus (DG), believed to be important for social processing, and to the dorsal DG, believed to be important for spatial and contextual processing. The hippocampus provides direct inhibitory input to the SuM, but the nature and function of this connectivity is completely unknown. The studies outlined in the proposal would provide important basic science groundwork for understanding this connectivity, with ultimate potential impacts for better understanding and treating a range of neurological disorders, including but not limited to temporal lobe epilepsy. This includes examining the hippocampal neurons providing the inhibitory input to the SuM, examining which subpopulations of SuM neurons receive inhibitory hippocampal input, and the in vivo impact of manipulation of inhibitory hippocampal inputs to the SuM. Based on our preliminary data, we predict that there are at least two populations of hippocampal inhibitory neurons projecting to the SuM -- one expressing neuronal nitric oxide synthase (nNOS) and the other expressing somatostatin – located in each region and along the entire anterior-posterior axis of the hippocampus. We further predict the greatest number in the CA3 region. We predict, and our preliminary data supports, that both SuM cells projecting to the ventral DG and SuM cells projecting to the dorsal DG receive inhibitory hippocampal inputs. Importantly, we see the strongest connectivity so far from the ventral hippocampus to SuM neurons projecting to the dorsal DG, arguing against a simple feedback inhibitory role of this connection. To examine the function of inhibitory hippocampal inputs to the SuM in vivo, we will use fiberphotometry to record from projection-defined SuM populations, during an assortment of behavioral tests, while providing closed-loop optogenetic manipulation of inhibitory hippocampal inputs specifically at the time of object or conspecific investigations. Collectively, the data will provide important insights into the nature of hippocampal inhibitory inputs to the SuM, including the degree to which specific SuM populations are targeted, and the functional significance of this connectivity, including as relates to social and spatial processing.
