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

目标导向导航过程中的决策是一种高度进化的行为，需要协调感知、学习和记忆以及计划。在过去的五个月里，通过使用一系列的电路询问技术，包括病毒追踪和光遗传学，我们已经成功地确定了从下丘脑乳头体上核（SuM）到海马齿状回（DG）的神经回路在小鼠执行T-迷宫延迟不匹配到样本任务中的关键作用。这一重大进展填补差距的宽电路地图，桥梁海马作出决定，在空间navigation.At首先，我们进行了全脑三维映射的SuM传出利用SuM-Cre转基因小鼠系，允许特异性表达的荧光蛋白在SuM。脑组织清除后，实现了SuM传出神经的图谱的高分辨率重建，表明从SuM到DG的强烈投射。接下来，我们采用靶向光遗传学来测试SuM-DG回路在目标导向导航中的功能。将Cre依赖性通道视紫红质-2（ChR 2）或表达古视紫红质（ArchT）的腺相关病毒（AAV）注射至SuM。对于ChR 2转染的小鼠，在DG末端应用488 nm激光对任务表现没有影响。然而，当532 nm激光应用于ArchT转染小鼠时，我们发现T-迷宫性能急剧下降。这一结果清楚地表明，抑制的SuM-DG电路损害了动物的空间工作记忆在目标导向的导航。

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.