Liu Hongzhi, Shi Yun, Zhang Qi, Yue Meihui, Qi Yanqing, Xu Benlei, Jing Jiayu, Zhang Linhong, Yang Kangqi, Zheng Mingfang, Zhou Jingfeng, Lu Jiangteng, Gong Ling, He Miao
Institutes of Brain Science, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Department of Neurobiology, Zhongshan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Mol Psychiatry. 2025 Jun 23. doi: 10.1038/s41380-025-03079-w.
The medial mammillary body (MM) is an integral component of the Papez circuit and the extended hippocampal system essential for cognitive and emotional functions. However, whether MM contains morpho-electrophysiologically distinguishable, genetically identifiable neuron types, and how they interact to process information underlying diverse MM functions, has remained largely unexplored. Here we employed a multidisciplinary approach in mice, combing genetic labeling, electrophysiological recording, morphological reconstruction, viral tracing, activity monitoring and manipulation, and behavioral testing to perform an integrative analysis of MM. We identified two major neuron types in MM, distinguished by the expression of calbindin (CB) and parvalbumin (PV). These neuron types occupy complementary MM territories and exhibit discernable anatomical and physiological characteristics. Further, they display segregated outputs and differential inputs, with scarce local connectivity, forming independent subcircuits for parallel information processing. Using optogenetic activation and calcium fiber photometry, we demonstrated that CB-expressing MM neurons, but not PV-expressing ones, drive place aversion and hyperlocomotion and exhibit elevated activity during locomotion. In summary, our findings reveal the neuronal composition of MM, delineate its local and long-range circuit organization, and uncover functionally divergent, cell-type-specific subcircuits, establishing a robust framework for future investigations in both healthy and diseased states.
内侧乳头体（MM）是帕佩兹环路和扩展海马系统的一个组成部分，对认知和情感功能至关重要。然而，MM是否包含形态电生理上可区分、基因上可识别的神经元类型，以及它们如何相互作用以处理多种MM功能背后的信息，在很大程度上仍未得到探索。在这里，我们在小鼠中采用了多学科方法，结合基因标记、电生理记录、形态重建、病毒示踪、活动监测与操纵以及行为测试，对MM进行综合分析。我们在MM中鉴定出两种主要的神经元类型，以钙结合蛋白（CB）和小白蛋白（PV）的表达为特征。这些神经元类型占据互补的MM区域，并表现出可辨别的解剖和生理特征。此外，它们显示出分离的输出和不同的输入，局部连接稀少，形成独立的子回路用于并行信息处理。通过光遗传学激活和钙纤维光度法，我们证明表达CB的MM神经元而非表达PV的神经元会引发位置厌恶和运动亢进，并在运动过程中表现出活动增强。总之，我们的研究结果揭示了MM的神经元组成，描绘了其局部和长程回路组织，并发现了功能不同、细胞类型特异性的子回路，为未来在健康和疾病状态下的研究建立了一个强大的框架。
