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Cellular mechanisms of spatial navigation in the medial entorhinal cortex

Nature Neuroscience volume 16, pages 325–331 (2013)Cite this article

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Abstract

Neurons in the medial entorhinal cortex exhibit a grid-like spatial pattern of spike rates that has been proposed to represent a neural code for path integration. To understand how grid cell firing arises from the combination of intrinsic conductances and synaptic input in medial entorhinal stellate cells, we performed patch-clamp recordings in mice navigating in a virtual-reality environment. We found that the membrane potential signature of stellate cells during firing field crossings consisted of a slow depolarization driving spike output. This was best predicted by network models in which neurons receive sustained depolarizing synaptic input during a field crossing, such as continuous attractor network models of grid cell firing. Another key feature of the data, phase precession of intracellular theta oscillations and spiking with respect to extracellular theta oscillations, was best captured by an oscillatory interference model. Thus, these findings provide crucial new information for a quantitative understanding of the cellular basis of spatial navigation in the entorhinal cortex.

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Figure 1: Patch-clamp recordings from MEC neurons in navigating mice.
Figure 2: Stellate cell membrane potential shows no prominent theta periodicity in resting mice.
Figure 3: Stellate cells exhibit theta membrane potential oscillations during running.
Figure 4: Sustained depolarizations drive stellate cell firing.
Figure 5: Comparing experimental data with grid cell models.
Figure 6: The spiking mechanism in stellate cells is compatible with a CAN model of grid cell firing.
Figure 7: Rate and temporal code of grid cell firing are reproduced by a hybrid CAN and oscillatory interference model.

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References

  1. 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).

    Article  CAS  Google Scholar 

  2. Sargolini, F. et al. Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312, 758–762 (2006).

    Article  CAS  Google Scholar 

  3. Fyhn, M., Hafting, T., Witter, M.P., Moser, E.I. & Moser, M.B. Grid cells in mice. Hippocampus 18, 1230–1238 (2008).

    Article  Google Scholar 

  4. Hafting, T., Fyhn, M., Bonnevie, T., Moser, M.B. & Moser, E.I. Hippocampus-independent phase precession in entorhinal grid cells. Nature 453, 1248–1252 (2008).

    Article  CAS  Google Scholar 

  5. Reifenstein, E.T., Kempter, R., Schreiber, S., Stemmler, M.B. & Herz, A.V. Grid cells in rat entorhinal cortex encode physical space with independent firing fields and phase precession at the single-trial level. Proc. Natl. Acad. Sci. USA 109, 6301–6306 (2012).

    Article  CAS  Google Scholar 

  6. Fuhs, M.C. & Touretzky, D.S. A spin glass model of path integration in rat medial entorhinal cortex. J. Neurosci. 26, 4266–4276 (2006).

    Article  CAS  Google Scholar 

  7. McNaughton, B.L., Battaglia, F.P., Jensen, O., Moser, E.I. & Moser, M.B. Path integration and the neural basis of the 'cognitive map'. Nat. Rev. Neurosci. 7, 663–678 (2006).

    Article  CAS  Google Scholar 

  8. Burgess, N. Grid cells and theta as oscillatory interference: theory and predictions. Hippocampus 18, 1157–1174 (2008).

    Article  Google Scholar 

  9. Burgess, N., Barry, C. & O'Keefe, J. An oscillatory interference model of grid cell firing. Hippocampus 17, 801–812 (2007).

    Article  Google Scholar 

  10. Hasselmo, M.E., Giocomo, L.M. & Zilli, E.A. Grid cell firing may arise from interference of theta frequency membrane potential oscillations in single neurons. Hippocampus 17, 1252–1271 (2007).

    Article  Google Scholar 

  11. Navratilova, Z., Giocomo, L.M., Fellous, J.M., Hasselmo, M.E. & McNaughton, B.L. Phase precession and variable spatial scaling in a periodic attractor map model of medial entorhinal grid cells with realistic after-spike dynamics. Hippocampus 22, 772–789 (2012).

    Article  Google Scholar 

  12. Burak, Y. & Fiete, I.R. Accurate path integration in continuous attractor network models of grid cells. PLoS Comput. Biol. 5, e1000291 (2009).

    Article  Google Scholar 

  13. Hölscher, C., Schnee, A., Dahmen, H., Setia, L. & Mallot, H.A. Rats are able to navigate in virtual environments. J. Exp. Biol. 208, 561–569 (2005).

    Article  Google Scholar 

  14. Harvey, C.D., Collman, F., Dombeck, D.A. & Tank, D.W. Intracellular dynamics of hippocampal place cells during virtual navigation. Nature 461, 941–946 (2009).

    Article  CAS  Google Scholar 

  15. Brun, V.H. et al. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18, 1200–1212 (2008).

    Article  Google Scholar 

  16. Alonso, A. & Klink, R. Differential electroresponsiveness of stellate and pyramidal-like cells of medial entorhinal cortex layer II. J. Neurophysiol. 70, 128–143 (1993).

    Article  CAS  Google Scholar 

  17. Garden, D.L., Dodson, P.D., O'Donnell, C., White, M.D. & Nolan, M.F. Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields. Neuron 60, 875–889 (2008).

    Article  CAS  Google Scholar 

  18. Giocomo, L.M., Zilli, E.A., Fransén, E. & Hasselmo, M.E. Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing. Science 315, 1719–1722 (2007).

    Article  CAS  Google Scholar 

  19. Fernandez, F.R. & White, J.A. Artificial synaptic conductances reduce subthreshold oscillations and periodic firing in stellate cells of the entorhinal cortex. J. Neurosci. 28, 3790–3803 (2008).

    Article  CAS  Google Scholar 

  20. Nolan, M.F., Dudman, J.T., Dodson, P.D. & Santoro, B. HCN1 channels control resting and active integrative properties of stellate cells from layer II of the entorhinal cortex. J. Neurosci. 27, 12440–12451 (2007).

    Article  CAS  Google Scholar 

  21. Quilichini, P., Sirota, A. & Buzsáki, G. Intrinsic circuit organization and theta-gamma oscillation dynamics in the entorhinal cortex of the rat. J. Neurosci. 30, 11128–11142 (2010).

    Article  CAS  Google Scholar 

  22. Welday, A.C., Shlifer, I.G., Bloom, M.L., Zhang, K. & Blair, H.T. Cosine directional tuning of theta cell burst frequencies: evidence for spatial coding by oscillatory interference. J. Neurosci. 31, 16157–16176 (2011).

    Article  CAS  Google Scholar 

  23. Zilli, E.A. & Hasselmo, M.E. Coupled noisy spiking neurons as velocity-controlled oscillators in a model of grid cell spatial firing. J. Neurosci. 30, 13850–13860 (2010).

    Article  CAS  Google Scholar 

  24. Pastoll, H., Solanka, L., van Rossum, M.C. & Nolan, M.F. Feedback inhibition enables theta-nested gamma oscillations and grid firing fields. Neuron 77, 141–154 (2013).

    Article  CAS  Google Scholar 

  25. Couey, J.J. et al. Recurrent inhibitory circuitry as a mechanism for grid formation. Nat. Neurosci. 10.1038/nn.3310 (2013).

  26. Mehta, M.R., Lee, A.K. & Wilson, M.A. Role of experience and oscillations in transforming a rate code into a temporal code. Nature 417, 741–746 (2002).

    Article  CAS  Google Scholar 

  27. Burgess, N. & O'Keefe, J. Models of place and grid cell firing and theta rhythmicity. Curr. Opin. Neurobiol. 21, 734–744 (2011).

    Article  CAS  Google Scholar 

  28. Koenig, J., Linder, A.N., Leutgeb, J.K. & Leutgeb, S. The spatial periodicity of grid cells is not sustained during reduced theta oscillations. Science 332, 592–595 (2011).

    Article  CAS  Google Scholar 

  29. Brandon, M.P. et al. Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning. Science 332, 595–599 (2011).

    Article  CAS  Google Scholar 

  30. Haas, J.S. & White, J.A. Frequency selectivity of layer II stellate cells in the medial entorhinal cortex. J. Neurophysiol. 88, 2422–2429 (2002).

    Article  Google Scholar 

  31. Kropff, E. & Treves, A. The emergence of grid cells: intelligent design or just adaptation? Hippocampus 18, 1256–1269 (2008).

    Article  Google Scholar 

  32. Zilli, E.A. Models of grid cell spatial firing published 2005–2011. Front. Neural Circuits 6, 16 (2012).

    Article  Google Scholar 

  33. O'Keefe, J. & Recce, M.L. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3, 317–330 (1993).

    Article  CAS  Google Scholar 

  34. Hasselmo, M.E. & Brandon, M.P. A model combining oscillations and attractor dynamics for generation of grid cell firing. Front. Neural Circuits 6, 30 (2012).

    Article  Google Scholar 

  35. Yartsev, M.M., Witter, M.P. & Ulanovsky, N. Grid cells without theta oscillations in the entorhinal cortex of bats. Nature 479, 103–107 (2011).

    Article  CAS  Google Scholar 

  36. Dodson, P.D., Pastoll, H. & Nolan, M.F. Dorsal-ventral organization of theta-like activity intrinsic to entorhinal stellate neurons is mediated by differences in stochastic current fluctuations. J. Physiol. (Lond.) 589, 2993–3008 (2011).

    Article  CAS  Google Scholar 

  37. Bourke, P. Spherical mirror: a new approach to hemispherical dome projection. Planetarian 34, 6–9 (2005).

    Google Scholar 

  38. Wagor, E., Mangini, N.J. & Pearlman, A.L. Retinotopic organization of striate and extrastriate visual cortex in the mouse. J. Comp. Neurol. 193, 187–202 (1980).

    Article  CAS  Google Scholar 

  39. Margrie, T.W., Brecht, M. & Sakmann, B. In vivo, low-resistance, whole-cell recordings from neurons in the anaesthetized and awake mammalian brain. Pflügers Arch. 444, 491–498 (2002).

    Article  CAS  Google Scholar 

  40. Klink, R. & Alonso, A. Morphological characteristics of layer II projection neurons in the rat medial entorhinal cortex. Hippocampus 7, 571–583 (1997).

    Article  CAS  Google Scholar 

  41. Kempter, R., Leibold, C., Buzsáki, G., Diba, K. & Schmidt, R. Quantifying circular-linear associations: hippocampal phase precession. J. Neurosci. Methods 207, 113–124 (2012).

    Article  Google Scholar 

  42. Carnevale, N.T. & Hines, M.L. The NEURON Book (Cambridge University Press, 2006).

    Book  Google Scholar 

  43. Fransén, E., Alonso, A.A., Dickson, C.T., Magistretti, J. & Hasselmo, M.E. Ionic mechanisms in the generation of subthreshold oscillations and action potential clustering in entorhinal layer II stellate neurons. Hippocampus 14, 368–384 (2004).

    Article  Google Scholar 

  44. Katz, Y. et al. Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons. Neuron 63, 171–177 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to N. Burgess, B. Clark, P. Dayan, K. Harris, P. Latham, J. O'Keefe, A. Packer, A. Roth, S. Turaga and C. Wilms for helpful discussions and for comments on the manuscript, and to A. Naeem for assistance with histology. This work was supported by grants from the Wellcome Trust, European Research Council and Gatsby Charitable Foundation, and by a fellowship to C. S.-H. from the Alexander von Humboldt Foundation.

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Authors and Affiliations

  1. Wolfson Institute for Biomedical Research, University College London, London, UK

    Christoph Schmidt-Hieber & Michael Häusser

  2. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Christoph Schmidt-Hieber & Michael Häusser

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C.S.-H. and M.H. designed the study, interpreted the results and wrote the paper. C.S.-H. performed the experiments, analysis and modeling.

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Correspondence to Christoph Schmidt-Hieber or Michael Häusser.

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Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Table 1 (PDF 13164 kb)

Supplementary Video 1

Video of mouse navigation in virtual reality (MP4 5403 kb)

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Schmidt-Hieber, C., Häusser, M. Cellular mechanisms of spatial navigation in the medial entorhinal cortex. Nat Neurosci 16, 325–331 (2013). https://doi.org/10.1038/nn.3340

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