Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A dorsal subiculum-medial mammillary body pathway for spatial memory

Molecular Psychiatry (2025)Cite this article

Subjects

Abstract

The dorsal subiculum (dSub) and medial mammillary body (MM) are essential components of the extended hippocampal system, heavily implicated in spatial memory processes. However, the exact function of the prominent dSub-to-MM projection has remained ambiguous. Here, integrating c-fos mapping, fiber photometry, optogenetic manipulations and behavioral paradigms, we found that the monosynaptic connection between dSub and MM, rather than collaterals to other regions, is not only involved in spatial memory retrieval but also highly vulnerable to perturbations on activity level in both directions. In addition, we mapped the single neuron projectome of MM-projecting dSub neurons using fluorescence micro-optical sectioning tomography (fMOST). Our study unveiled that the individual dSub neuron extend efferent connections to the bilateral MM neurons, while also exhibiting substantial collateral projections to the retrosplenial cortex (RSP) and entorhinal (ENT). Our findings shed light on previously unknown subtypes and organizational principles of projection neurons in the afferent circuitry of the MM, thereby elucidating the circuit mechanism underlying the contribution of the dSub-MM circuit to spatial memory.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of dSub and MM participated in object-___location memory.
Fig. 2: Optogenetic manipulation of the dSub-MM circuit altered the response of MMdSub neurons to different object-locations.
Fig. 3: Optogenetic stimulation of the MMdSub neurons disrupted spatial memory.
Fig. 4: The whole-brain inputs to the MM and long-range projectional patterns of input neurons.

Similar content being viewed by others

Data availability

All the data that support the findings of this study are provided in the article and its supplementary information files and source data. Raw data for neuron reconstruction is available at http://atlas.brainsmatics.org/a/sun2112. Source data are provided with this paper. Additional information about this paper are available from the corresponding author upon reasonable request.

Code availability

The code for image processing is available in previous studies [22, 51], which can be found from http://atlas.brainsmatics.org/a/zhong2019.

References

  1. Winnubst J, Bas E, Ferreira TA, Wu Z, Economo MN, Edson P, et al. Reconstruction of 1000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain. Cell. 2019;179:268–81.e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Umaba R, Kitanishi T, Mizuseki K. Monosynaptic connection from the subiculum to medial mammillary nucleus neurons projecting to the anterior thalamus and Gudden’s ventral tegmental nucleus. Neurosci Res. 2021;171:1–8.

    Article  CAS  PubMed  Google Scholar 

  3. Aggleton JP, Christiansen K. The subiculum: the heart of the extended hippocampal system. Prog Brain Res. 2015;219:65–82.

    Article  PubMed  Google Scholar 

  4. Kitanishi T, Umaba R, Mizuseki K. Robust information routing by dorsal subiculum neurons. Sci Adv. 2021;7:eabf1913.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Roy DS, Kitamura T, Okuyama T, Ogawa SK, Sun C, Obata Y, et al. Distinct neural circuits for the formation and retrieval of episodic memories. Cell. 2017;170:1000–12.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sun Y, Jin S, Lin X, Chen L, Qiao X, Jiang L, et al. CA1-projecting subiculum neurons facilitate object–place learning. Nat Neurosci. 2019;22:1857–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thierry M, Boluda S, Delatour B, Marty S, Seilhean D, Brainbank Neuro-CEB Neuropathology Network. et al. Human subiculo-fornico-mamillary system in Alzheimer’s disease: tau seeding by the pillar of the fornix. Acta Neuropathol. 2020;139:443–61.

    Article  CAS  PubMed  Google Scholar 

  8. Mathiasen ML, Louch RC, Nelson AD, Dillingham CM, Aggleton JP. Trajectory of hippocampal fibres to the contralateral anterior thalamus and mammillary bodies in rats, mice, and macaque monkeys. Brain Neurosci Adv. 2019;3:2398212819871205.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vann SD. Dismantling the Papez circuit for memory in rats. eLife. 2013;2:e00736.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kinnavane L, Vann SD, Nelson AJD, O’Mara SM, Aggleton JP. Collateral Projections innervate the mammillary bodies and retrosplenial cortex: a new category of hippocampal cells. eNeuro. 2018;5:ENEURO.0383-17.

    Article  Google Scholar 

  11. Nelson AJD, Vann SD. Mammilliothalamic tract lesions disrupt tests of visuo-spatial memory. Behav Neurosci. 2014;128:494–503.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gutiérrez-Guzmán BE, Hernández-Pérez JJ, Olvera-Cortés ME. Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat. Behav Brain Res. 2017;319:73–86.

    Article  PubMed  Google Scholar 

  13. Santı́n LJ, Rubio S, Begega A, Arias JL. Effects of mammillary body lesions on spatial reference and working memory tasks. Behav Brain Res. 1999;102:137–50.

    Article  PubMed  Google Scholar 

  14. Dillingham CM, Milczarek MM, Perry JC, Frost BE, Parker GD, Assaf Y, et al. Mammillothalamic disconnection alters hippocampocortical oscillatory activity and microstructure: implications for diencephalic amnesia. J Neurosci. 2019;39:6696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang J, Long B, Li A, Sun Q, Tian J, Luo T, et al. Whole-brain three-dimensional profiling reveals brain region specific axon vulnerability in 5xFAD mouse model. Front Neuroanat. 2020;14:1–14.

    Article  Google Scholar 

  16. Tsivilis D, Vann SD, Denby C, Roberts N, Mayes AR, Montaldi D, et al. A disproportionate role for the fornix and mammillary bodies in recall versus recognition memory. Nat Neurosci. 2008;11:834–42.

    Article  CAS  PubMed  Google Scholar 

  17. Vann SD, Erichsen JT, O’Mara SM, Aggleton JP. Selective disconnection of the hippocampal formation projections to the mammillary bodies produces only mild deficits on spatial memory tasks: implications for fornix function. Hippocampus. 2011;21:945–57.

    Article  PubMed  Google Scholar 

  18. Kocsis B, Vertes R. Characterization of neurons of the supramammillary nucleus and mammillary body that discharge rhythmically with the hippocampal theta rhythm in the rat. J Neurosci. 1994;14:7040–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vann SD, Aggleton JP. The mammillary bodies: two memory systems in one? Nat Rev Neurosci. 2004;5:35–44.

    Article  CAS  PubMed  Google Scholar 

  20. Żakowski W, Braszka Ł, Zawistowski P, Orzeł-Gryglewska J, Jurkowlaniec E. Inactivation of the medial mammillary nucleus attenuates theta rhythm activity in the hippocampus in urethane-anesthetized rats. Neurosci Lett. 2017;645:19–24.

    Article  PubMed  Google Scholar 

  21. Qiu L, Zhang B, Gao Z. Lighting up neural circuits by viral tracing. Neurosci Bull. 2022;38:1383–96.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gong H, Xu D, Yuan J, Li X, Guo C, Peng J, et al. High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level. Nat Commun. 2016;7:12142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang X, Jiang T, Liu L, Zhao X, Yu X, Yang M, et al. Observing single cells in whole organs with optical imaging. J Innov Opt Health Sci. 2022;16:2330002.

    Article  Google Scholar 

  24. Sun Q, Zhang J, Li A, Yao M, Liu G, Chen S, et al. Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer’s disease. Nat Commun. 2022;13:998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Etter G, van der Veldt S, Manseau F, Zarrinkoub I, Trillaud-Doppia E, Williams S. Optogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model. Nat Commun. 2019;10:5322.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Trimper JB, Galloway CR, Jones AC, Mandi K, Manns JR. Gamma oscillations in rat hippocampal subregions dentate gyrus, CA3, CA1, and subiculum underlie associative memory encoding. Cell Rep. 2017;21:2419–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang C, Zhu H, Ni Z, Xin Q, Zhou T, Wu R, et al. Dynamics of a disinhibitory prefrontal microcircuit in controlling social competition. Neuron. 2022;110:516–31.e6.

    Article  CAS  PubMed  Google Scholar 

  28. Li Y, Gong H, Yang X, Yuan J, Jiang T, Li X, et al. TDat: an efficient platform for processing petabyte-scale whole-brain volumetric images. Front Neural Circuits. 2017;11:51.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhou H, Li S, Li A, Huang Q, Xiong F, Li N, et al. GTree: an open-source tool for dense reconstruction of brain-wide neuronal population. Neuroinformatics. 2021;19:305–17.

    Article  PubMed  Google Scholar 

  30. Fei F, Wang X, Xu C, Shi J, Gong Y, Cheng H, et al. Discrete subicular circuits control generalization of hippocampal seizures. Nat Commun. 2022;13:5010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen S, He L, Huang AJY, Boehringer R, Robert V, Wintzer ME, et al. A hypothalamic novelty signal modulates hippocampal memory. Nature. 2020;586:270–4.

    Article  CAS  PubMed  Google Scholar 

  32. Vetere G, Xia F, Ramsaran AI, Tran LM, Josselyn SA, Frankland PW. An inhibitory hippocampal–thalamic pathway modulates remote memory retrieval. Nat Neurosci. 2021;24:685–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vann SD. Re-evaluating the role of the mammillary bodies in memory. Neuropsychologia. 2010;48:2316–27.

    Article  PubMed  Google Scholar 

  34. Dillingham CM, Milczarek MM, Perry JC, Vann SD. Time to put the mammillothalamic pathway into context. Neurosci Biobehav Rev. 2021;121:60–74.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Vann SD, Nelson AJD. The mammillary bodies and memory: more than a hippocampal relay. Progress in brain research. 2015;219:163–85.

  36. Cembrowski MS, Phillips MG, DiLisio SF, Shields BC, Winnubst J, Chandrashekar J, et al. Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes. Cell. 2018;174:1036.

    Article  CAS  PubMed  Google Scholar 

  37. Kim Y, Yang GR, Pradhan K, Venkataraju KU, Bota M, García del Molino LC, et al. Brain-wide maps reveal stereotyped cell-type-based cortical architecture and subcortical sexual dimorphism. Cell. 2017;171:456–69.e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mickelsen LE, Flynn WF, Springer K, Wilson L, Beltrami EJ, Bolisetty M, et al. Cellular taxonomy and spatial organization of the murine ventral posterior hypothalamus. eLife. 2020;9:e58901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Aggleton JP, Nelson AJD, O’Mara SM. Time to retire the serial Papez circuit: Implications for space, memory, and attention. Neurosci Biobehav Rev. 2022;140:104813.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Dillingham CM, Frizzati A, Nelson AJD, Vann SD. How do mammillary body inputs contribute to anterior thalamic function? Neurosci Biobehav Rev. 2015;54:108–19.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gail Canter R, Huang W-C, Choi H, Wang J, Ashley Watson L, Yao CG, et al. 3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice. Commun Biol. 2019;2:360.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mathiasen ML, Amin E, Nelson AJD, Dillingham CM, O’Mara SM, Aggleton JP. Separate cortical and hippocampal cell populations target the rat nucleus reuniens and mammillary bodies. Eur J Neurosci. 2019;49:1649–72.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nat Neurosci. 2015;18:1394–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tingley D, Buzsáki G. Transformation of a spatial map across the hippocampal-lateral septal circuit. Neuron. 2018;98:1229–42.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vann SD, Aggleton JP, Maguire EA. What does the retrosplenial cortex do? Nat Rev Neurosci. 2009;10:792–802.

    Article  CAS  PubMed  Google Scholar 

  46. Alexander A, Soltesz I. Hippogate: a break-in from entorhinal cortex. Nat Neurosci. 2016;19:530–2.

    Article  CAS  PubMed  Google Scholar 

  47. van Groen T, Kadish I, Wyss JM. Retrosplenial cortex lesions of area Rgb (but not of area Rga) impair spatial learning and memory in the rat. Behav Brain Res. 2004;154:483–91.

    Article  PubMed  Google Scholar 

  48. Vann SD, Aggleton JP. Selective dysgranular retrosplenial cortex lesions in rats disrupt allocentric performance of the radial-arm maze task. Behav Neurosci. 2005;119:1682–6.

    Article  PubMed  Google Scholar 

  49. Tian J, Ren M, Zhao P, Luo S, Chen Y, Xu X, et al. Dissection of the long-range projections of specific neurons at the synaptic level in the whole mouse brain. Proc Natl Acad Sci USA. 2022;119:e2202536119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Aggleton JP, O’Mara SM. The anterior thalamic nuclei: core components of a tripartite episodic memory system. Nat Rev Neurosci. 2022;23:505–16.

    Article  CAS  PubMed  Google Scholar 

  51. Zhong Q, Li A, Jin R, Zhang D, Li X, Jia X, et al. High-definition imaging using line-illumination modulation microscopy. Nat Methods. 2021;18:309–15.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the members of HUST-Suzhou Institute for Brainsmatics for help with data acquisition on the neuron reconstruction. This work was financially supported by STI2030-Major Projects (Nos. 2022ZD0205201 and 2022ZD0206500), National Natural Science Foundation of China (Nos. 32400850), Hainan Natural Science Foundation of China (Nos. 822QN298), China Postdoctoral Science Foundation (Nos. 2022M710989), Hainan Postdoctoral Science Foundation (Nos. 2022–32) and Innovational Fund for Scientific and Technological Personnel of Hainan Province (KJRC2023A03).

Author information

Author notes

  1. These authors contributed equally: Jianping Zhang, Mei Yao.

Authors and Affiliations

  1. State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Haikou, China

    Jianping Zhang, Qingming Luo & Xiangning Li

  2. Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Jianping Zhang

  3. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China

    Mei Yao, Anan Li & Hui Gong

  4. HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, China

    Tao Jiang, Anan Li, Hui Gong & Xiangning Li

  5. Institutes of Brain Science, Department of Neurology, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Zhongshan Hospital, Fudan University, Shanghai, China

    Miao He

Authors
  1. Jianping Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Mei Yao
    View author publications

    Search author on:PubMed Google Scholar

  3. Tao Jiang
    View author publications

    Search author on:PubMed Google Scholar

  4. Anan Li
    View author publications

    Search author on:PubMed Google Scholar

  5. Hui Gong
    View author publications

    Search author on:PubMed Google Scholar

  6. Miao He
    View author publications

    Search author on:PubMed Google Scholar

  7. Qingming Luo
    View author publications

    Search author on:PubMed Google Scholar

  8. Xiangning Li
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XL, HG, JZ and QL conceived and designed the study. JZ and MY performed most of the experiments and analyzed the data. TJ performed the whole-brain data acquisition. AL performed the imaging processing and neuron reconstruction. JZ, XL, MH, HG and QL wrote the paper.

Corresponding authors

Correspondence to Miao He, Qingming Luo or Xiangning Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations of the Animal Care and Use Committee of Hainan University (HNUAUCC-2022-00032). The informed consent was obtained from all participants. There were no identifiable images from human research participants.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Yao, M., Jiang, T. et al. A dorsal subiculum-medial mammillary body pathway for spatial memory. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03087-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-025-03087-w

Search

Advanced search

Quick links