Deciphering a hypothalamo-hippocampal circuit in goal-directed spatial navigation

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Decision-making during goal-directed navigation is a highly evolved behavior requiring a coordination of perception, learning and memory, and planning. In the past five months, by using an array of circuit interrogation techniques including viral tracing and optogenetics, we have successfully identified a crucial role of the neural circuit from hypothalamic supramammillary nucleus (SuM) to hippocampal dentate gyrus (DG) in mice performing a T-maze delayed non-match to sample task. This significant progress has filled the gap on a wide circuit map that bridge to the hippocampus for making decisions during spatial navigation.At first, we performed brain-wide 3D mapping of SuM efferents by taking advantage of a SuM-Cre transgenic mouse line that allows specific expression of fluorescent proteins at SuM. After brain tissue clearing, high-resolution reconstruction of an atlas of SuM efferents was achieved, indicating strong projections from SuM to DG.Next, we employed targeted optogenetics to test the function of SuM-DG circuit in goal-directed navigation. Cre-dependent channelrhodopsin-2 (ChR2) or archaerhodopsin (ArchT)-expressing adeno-associated virus (AAV) was injected to SuM. For the ChR2-transfected mice, application of 488 nm laser at DG terminals showed no effect on the task performance. However, when 532 nm laser was applied to the ArchT-transfected mice, we found a dramatic decline of the T-maze performance. This result clearly indicated that inhibition of the SuM-DG circuit impaired the animal’s spatial working memory during goal-directed navigation.