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.

Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex

Abstract

The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object–location memory task. We identified ‘memory-trace cells’ with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Task overview.
Fig. 2: Examples of place and memory-trace cells.
Fig. 3: Place cell activity.
Fig. 4: Trace-fields shift according to memory for cued object locations.
Fig. 5: Memory-trace cells track subjective memory during retrieval.
Fig. 6: Memory-trace cell activity is correlated between the hold period and response period.
Fig. 7: Entorhinal cortex memory-trace cell activity predicts cued memory across hold and response periods.

Data availability

The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available because they could compromise research participant privacy and consent.

Code availability

Task was coded using the publicly available programming library PandaEPL64. Analysis was performed in Matlab and spike sorting in Python using the publicly available software package Combinato52. Analysis code is available on reasonable request from the corresponding author.

References

  1. 1.

    Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Squire, L. R., Knowlton, B. & Musen, G. The structure and organization of memory. Annu. Rev. Psychol. 44, 453–495 (1993).

    CAS  PubMed  Google Scholar 

  3. 3.

    O’Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map. (Oxford University Press, 1978).

  4. 4.

    Buzsaki, G. & Moser, E. Memory, navigation and theta rhythm in the hippocampal–entorhinal system. Nat. Neurosci. 16, 130–138 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    O’Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map: preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).

    Google Scholar 

  6. 6.

    Hafting, T., Fyhn, M., Molden, S., Moser, M.-B. & Moser, E. I. Microstructure of a spatial map in the entorhinal cortex. Nature 436, 801–806 (2005).

    CAS  PubMed  Google Scholar 

  7. 7.

    Leutgeb, S., Leutgeb, J. K., Treves, A., Moser, M.-B. & Moser, E. I. Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305, 1295–1298 (2004).

    CAS  PubMed  Google Scholar 

  8. 8.

    Colgin, L., Moser, E. & Moser, M. Understanding memory through hippocampal remapping. Trends Neurosci. 31, 469–477 (2008).

    CAS  PubMed  Google Scholar 

  9. 9.

    Markus, E. J. et al. Interactions between location and task affect the spatial and directional firing of hippocampal neurons. J. Neurosci. 15, 7079 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Dupret, D., O’Neill, J., Pleydell-Bouverie, B. & Csicsvari, J. The reorganization and reactivation of hippocampal maps predict spatial memory performance. Nat. Neurosci. 13, 995–1002 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Gauthier, J. L. & Tank, D. W. A dedicated population for reward coding in the hippocampus. Neuron 99, 179–193.e7 (2018).

    CAS  PubMed  Google Scholar 

  12. 12.

    Sugar, J. & Moser, M.-B. Episodic memory: neuronal codes for what, where, and when. Hippocampus https://doi.org/10.1002/hipo.23132 (2019).

    PubMed  Google Scholar 

  13. 13.

    Jacobs, J. et al. Direct recordings of grid-like neuronal activity in human spatial navigation. Nat. Neurosci. 16, 1188–1190 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Brun, V. et al. Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry. Science 296, 2243 (2002).

    CAS  PubMed  Google Scholar 

  15. 15.

    Chao, O. Y., Huston, J. P., Li, J.-S., Wang, A.-L. & de Souza Silva, M. A. The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition. Hippocampus 26, 633–645 (2016).

    PubMed  Google Scholar 

  16. 16.

    Knierim, J. J., Neunuebel, J. P. & Deshmukh, S. S. Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130369 (2014).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Behrens, T. E. J. et al. What is a cognitive map? Organizing knowledge for flexible behavior. Neuron 100, 490–509 (2018).

    CAS  PubMed  Google Scholar 

  18. 18.

    Tsao, A., Moser, M.-B. & Moser, E. I. Traces of experience in the lateral entorhinal cortex. Curr. Biol. 23, 399–405 (2013).

    CAS  PubMed  Google Scholar 

  19. 19.

    Kunz, L. et al. Reduced grid-cell–like representations in adults at genetic risk for Alzheimer’s disease. Science 350, 430–433 (2015).

    CAS  PubMed  Google Scholar 

  20. 20.

    Butler, W. N., Hardcastle, K. & Giocomo, L. M. Remembered reward locations restructure entorhinal spatial maps. Science 363, 1447–1452 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Ekstrom, A. D. et al. Cellular networks underlying human spatial navigation. Nature 425, 184–187 (2003).

    CAS  PubMed  Google Scholar 

  22. 22.

    Kraus, B. J. et al. During running in place, grid cells integrate elapsed time and distance run. Neuron 88, 578–589 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kropff, E., Carmichael, J. E., Moser, M.-B. & Moser, E. I. Speed cells in the medial entorhinal cortex. Nature 523, 419–424 (2015).

    CAS  PubMed  Google Scholar 

  24. 24.

    Robitsek, R., White, J. & Eichenbaum, H. Place cell activation predicts subsequent memory. Behavioural Brain Res. 254, 65–72 (2013).

    Google Scholar 

  25. 25.

    Sakai, K. & Miyashita, Y. Neural organization for the long-term memory of paired associates. Nature 354, 152–155 (1991).

    CAS  PubMed  Google Scholar 

  26. 26.

    O’Keefe, J. & Speakman, A. Single unit activity in the rat hippocampus during a spatial memory task. Exp. Brain Res 68, 1–27 (1987).

    PubMed  Google Scholar 

  27. 27.

    Skaggs, W. E, McNaughton, B. L, Gothard, K. M. & Markus, E. J. (eds Hanson, S. J., Cowan, J. D. & Giles, C. L.,). An information-theoretic approach to deciphering the hippocampal code. Adv. Neural Inf. Process. Syst. 5, 1030–1037 (1993).

  28. 28.

    Stachenfeld, K. L., Botvinick, M. M. & Gershman, S. J. The hippocampus as a predictive map. Nat. Neurosci. 20, 1643–1653 (2017).

    CAS  PubMed  Google Scholar 

  29. 29.

    Sarel, A., Finkelstein, A., Las, L. & Ulanovsky, N. Vectorial representation of spatial goals in the hippocampus of bats. Science 355, 176–180 (2017).

    CAS  PubMed  Google Scholar 

  30. 30.

    Mauritz, K. H. & Wise, S. P. Premotor cortex of the rhesus monkey: neuronal activity in anticipation of predictable environmental events. Exp. Brain Res. 61, 229–244 (1986).

    CAS  PubMed  Google Scholar 

  31. 31.

    Theeuwes, J., Kramer, A. F. & Irwin, D. E. Attention on our mind: the role of spatial attention in visual working memory. Acta Psychol. (Amst.) 137, 248–251 (2011).

    Google Scholar 

  32. 32.

    Kriegeskorte, N. Pattern-information analysis: from stimulus decoding to computational-model testing. Neuroimage 56, 411–421 (2011).

    PubMed  Google Scholar 

  33. 33.

    Muller, R. U. & Kubie, J. L. The effects of changes in the environment on the spatial firing of hippocampal complex-spike cells. J. Neurosci. 7, 1951–1968 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Leutgeb, S. et al. Independent codes for spatial and episodic memory in hippocampal neuronal ensembles. Science 309, 619–623 (2005).

    CAS  PubMed  Google Scholar 

  35. 35.

    Burke, S. N. et al. The influence of objects on place field expression and size in distal hippocampal ca1. Hippocampus 21, 783–801 (2011).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hollup, S., Molden, S., Donnett, J., Moser, M. & Moser, E. Accumulation of hippocampal place fields at the goal location in an annular watermaze task. J. Neurosci. 21, 1635–1644 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Suzuki, W. A., Miller, E. K. & Desimone, R. Object and place memory in the macaque entorhinal cortex. J. Neurophysiol. 78, 1062–1081 (1997).

    CAS  PubMed  Google Scholar 

  38. 38.

    Weible, A. P., Rowland, D. C., Pang, R. & Kentros, C. Neural correlates of novel object and novel location recognition behavior in the mouse anterior cingulate cortex. J. Neurophysiol. 102, 2055–2068 (2009).

    PubMed  Google Scholar 

  39. 39.

    Jacobs, J. et al. Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory. Neuron 92, 1–8 (2016).

    Google Scholar 

  40. 40.

    Goyal, A. et al. Electrical stimulation in hippocampus and entorhinal cortex impairs spatial and temporal memory. J. Neurosci. 38, 3049–17 (2018).

    Google Scholar 

  41. 41.

    Braak, H. & Braak, E. Neuropathological stageing of alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  42. 42.

    Gomez-Isla, T. et al. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci. 16, 4491 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Jacobs, H. I. L. et al. Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat. Neurosci. 21, 424–431 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Maass, A. et al. Entorhinal tau pathology, episodic memory decline, and neurodegeneration in aging. J. Neurosci. 38, 530–543 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Fu, H. et al. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93, 533–541.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Doeller, C. F., Barry, C. & Burgess, N. Evidence for grid cells in a human memory network. Nature 463, 657–661 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Maidenbaum, S., Miller, J., Stein, J. M. & Jacobs, J. Grid-like hexadirectional modulation of human entorhinal theta oscillations. Proc. Natl Acad. Sci. USA 115, 10798–10803 (2018).

    CAS  PubMed  Google Scholar 

  48. 48.

    Boccara, C. N., Nardin, M., Stella, F., O’Neill, J. & Csicsvari, J. The entorhinal cognitive map is attracted to goals. Science 363, 1443–1447 (2019).

    CAS  PubMed  Google Scholar 

  49. 49.

    Constantinescu, A. O., O’Reilly, J. X. & Behrens, T. E. J. Organizing conceptual knowledge in humans with a gridlike code. Science 352, 1464–1468 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Aronov, D., Nevers, R. & Tank, D. W. Mapping of a non-spatial dimension by the hippocampal–entorhinal circuit. Nature 543, 719 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Fried, I. et al. Cerebral microdialysis combined with single-neuron and electroencephalographic recording in neurosurgical patients. J. Neurosurg. 91, 697–705 (1999).

    CAS  PubMed  Google Scholar 

  52. 52.

    Niediek, J., Boström, J., Elger, C. E. & Mormann, F. Reliable analysis of single-unit recordings from the human brain under noisy conditions: tracking neurons over hours. PLoS One 11, e0166598 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Hill, D., Mehta, S. & Kleinfeld, D. Quality metrics to accompany spike sorting of extracellular signals. J. Neurosci. 31, 8699–8705 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Valdez, A. B., Hickman, E. N., Treiman, D. M., Smith, K. A. & Steinmetz, P. N. A statistical method for predicting seizure onset zones from human single-neuron recordings. J. Neural Eng. 10, 016001 (2013).

    PubMed  Google Scholar 

  55. 55.

    Lee, S. A. et al. Electrophysiological signatures of spatial boundaries in the human subiculum. J. Neurosci. 38, 3265–3272 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Wang, H. et al. Multi-atlas segmentation with joint label fusion. IEEE Trans. Pattern Anal. Mach. Intell. 35, 611–623 (2013).

    PubMed  Google Scholar 

  57. 57.

    Yushkevich, P. A. et al. Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment. Hum. Brain Mapp. 36, 258–287 (2015).

    PubMed  Google Scholar 

  58. 58.

    Avants, B. B., Epstein, C. L., Grossman, M. & Gee, J. C. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med. Image Anal. 12, 26–41 (2008).

    CAS  Google Scholar 

  59. 59.

    Kamin´ski, J. et al. Persistently active neurons in human medial frontal and medial temporal lobe support working memory. Nat. Neurosci. 20, 590–601 (2017).

    Google Scholar 

  60. 60.

    Fyhn, M., Molden, S., Witter, M., Moser, E. & Moser, M. Spatial representation in the entorhinal cortex. Science 305, 1258–1264 (2004).

    CAS  PubMed  Google Scholar 

  61. 61.

    Alme, C. B. et al. Place cells in the hippocampus: eleven maps for eleven rooms. Proc. Natl Acad. Sci. USA 111, 18428–18435 (2014).

    CAS  PubMed  Google Scholar 

  62. 62.

    Wilming, N., König, P., König, S. & Buffalo, E. A. Entorhinal cortex receptive fields are modulated by spatial attention, even without movement. Elife 7, e31745 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Holland, P. W. & Welsch, R. E. Robust regression using iteratively reweighted least-squares. Commun. Stat. Theory Methods A6, 813–827 (1977).

    Google Scholar 

  64. 64.

    Solway, A., Miller, J. F. & Kahana, M. J. PandaEPL: a library for programming spatial navigation experiments. Behav. Res. Methods 45, 1293–1312 (2013).

    PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients for participating in our study. This work was supported by NIH grants R01-MH104606 (to J.J.) and S10-OD018211 (to C.S.), NSF grants BCS-1724243 and BCS-1848465 (to J.J.), and NSF Graduate Research Fellowship DGE 16-44869 (to S.E.Q.). We thank Andrew Watrous (University of Texas, Austin), Melina Tsitsiklis (Columbia University), Ida Momennejad (Columbia University), Mariam Aly (Columbia University), Nicole Long (University of Virginia), and Niko Kriegeskorte (Columbia University) for helpful comments and suggestions.

Author information

Affiliations

Authors

Contributions

J.J. conceived the experiment; R.E.G., J.T.W., B.L., A.S., C.W., S.A.S., and G.M.M. performed surgical procedures; S.E.Q., J.M., M.R.S., C.S., E.H.S., J.-J.L., and C.S.I. performed data collection and recording; J.M.S. processed neuroimaging data; S.E.Q. analyzed the data; and S.E.Q. and J.J. wrote the manuscript.

Corresponding author

Correspondence to Joshua Jacobs.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Neuroscience thanks Stefan Leutgeb and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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

Supplementary information

Supplementary Information

Supplementary Figures 1–14 and Supplementary Tables 1 and 2.

Reporting Summary

Supplementary Video 1

This video depicts the task instructions that participants are given at the beginning of a session, followed by two encoding trials and one retrieval trial for an object.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Qasim, S.E., Miller, J., Inman, C.S. et al. Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex. Nat Neurosci 22, 2078–2086 (2019). https://doi.org/10.1038/s41593-019-0523-z

Download citation

Further reading

Search

Quick links