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:

Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex

Subjects

Abstract

In the hippocampus, spatial and non-spatial parameters may be represented by a dual coding scheme, in which coordinates in space are expressed by the collective firing locations of place cells and the diversity of experience at these locations is encoded by orthogonal variations in firing rates. Although the spatial signal may reflect input from medial entorhinal cortex, the sources of the variations in firing rate have not been identified. We found that rate variations in rat CA3 place cells depended on inputs from the lateral entorhinal cortex (LEC). Hippocampal rate remapping, induced by changing the shape or the color configuration of the environment, was impaired by lesions in those parts of the ipsilateral LEC that provided the densest input to the hippocampal recording position. Rate remapping was not observed in LEC itself. The findings suggest that LEC inputs are important for efficient rate coding in the hippocampus.

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

Access options

Buy this article

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

Figure 1: Neurotoxic damage in the LEC, recording positions in the hippocampus and their connectional relationships.
Figure 2: Example rate maps showing that LEC lesions abolish rate remapping in response to a change in the shape of the recording enclosure.
Figure 3: Average data showing impaired hippocampal rate remapping in LEC-lesioned rats.
Figure 4: Rate remapping depends on the location of the lesion in LEC.
Figure 5: LEC lesions impair progressive rate remapping during morphing of square and circular environments.
Figure 6: LEC lesions disrupt rate remapping between black and white versions of the same box.
Figure 7: Average data for the black-white task.
Figure 8: Lack of rate remapping in LEC neurons.

Similar content being viewed by others

References

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

  2. Moser, E.I., Kropff, E. & Moser, M.-B. Place cells, grid cells, and the brain's spatial representation system. Annu. Rev. Neurosci. 31, 69–89 (2008).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Wilson, M.A. & McNaughton, B.L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Young, B.J., Fox, G.D. & Eichenbaum, H. Correlates of hippocampal complex-spike activity in rats performing a nonspatial radial maze task. J. Neurosci. 14, 6553–6563 (1994).

    Article  CAS  Google Scholar 

  7. Wood, E.R., Dudchenko, P.A. & Eichenbaum, H. The global record of memory in hippocampal neuronal activity. Nature 397, 613–616 (1999).

    Article  CAS  Google Scholar 

  8. Komorowski, R.W., Manns, J.R. & Eichenbaum, H. Robust conjunctive item-place coding by hippocampal neurons parallels learning what happens where. J. Neurosci. 29, 9918–9929 (2009).

    Article  CAS  Google Scholar 

  9. Pastalkova, E., Itskov, V., Amarasingham, A. & Buzsáki, G. Internally generated cell assembly sequences in the rat hippocampus. Science 321, 1322–1327 (2008).

    Article  CAS  Google Scholar 

  10. MacDonald, C.J., Lepage, K.Q., Eden, U.T. & Eichenbaum, H. Hippocampal 'time cells' bridge the gap in memory for discontiguous events. Neuron 71, 737–749 (2011).

    Article  CAS  Google Scholar 

  11. Markus, E.J. et al. Interactions between location and task affect the spatial and directional firing of hippocampal neurons. J. Neurosci. 15, 7079–7094 (1995).

    Article  CAS  Google Scholar 

  12. Moita, M.A., Rosis, S., Zhou, Y., LeDoux, J.E. & Blair, H.T. Putting fear in its place; remapping of hippocampal place cells during fear conditioning. J. Neurosci. 24, 7015–7023 (2004).

    Article  CAS  Google Scholar 

  13. Leutgeb, S. et al. Independent codes for spatial and episodic memory in the hippocampus. Science 309, 619–623 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Hargreaves, E.L., Rao, G., Lee, I. & Knierim, J.J. Major dissociation between medial and lateral entorhinal input to the dorsal hippocampus. Science 308, 1792–1794 (2005).

    Article  CAS  Google Scholar 

  16. 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 

  17. Fyhn, M., Hafting, T., Treves, A., Moser, M.-B. & Moser, E.I. Hippocampal remapping and grid realignment in entorhinal cortex. Nature 446, 190–194 (2007).

    Article  CAS  Google Scholar 

  18. Stensola, H. et al. The entorhinal grid map is discretized. Nature 492, 72–78 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Young, B.J., Otto, T., Fox, G.D. & Eichenbaum, H. Memory representation within the parahippocampal region. J. Neurosci. 17, 5183–5195 (1997).

    Article  CAS  Google Scholar 

  21. Deshmukh, S.S. & Knierim, J.J. Representation of non-spatial and spatial information in the lateral entorhinal cortex. Front. Behav. Neurosci 5, 69 (2011).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Burke, S.N. et al. Representation of three-dimensional objects by the rat perirhinal cortex. Hippocampus 22, 2032–2044 (2012).

    Article  CAS  Google Scholar 

  24. Deshmukh, S.S., Johnson, J.L. & Knierim, J.J. Perirhinal cortex represents nonspatial, but not spatial, information in rats foraging in the presence of objects: comparison with lateral entorhinal cortex. Hippocampus 22, 2045–2058 (2012).

    Article  Google Scholar 

  25. Witter, M.P., Groenewegen, H.J., Lopes da Silva, F.H. & Lohman, A.H. Functional organization of the extrinsic and intrinsic circuitry of the parahippocampal region. Prog. Neurobiol. 33, 161–253 (1989).

    Article  CAS  Google Scholar 

  26. Dolorfo, C.L. & Amaral, D.G. Entorhinal cortex of the rat: topographic organization of the cells of origin of the perforant path projection to the dentate gyrus. J. Comp. Neurol. 398, 25–48 (1998).

    Article  CAS  Google Scholar 

  27. Witter, M.P. & Amaral, D.G. Hippocampal formation. in The Rat Nervous System 3rd edn. (ed. Paxinos, G.) 635–704 (Elsevier Academic Press, 2004).

  28. Leutgeb, J.K. et al. Progressive transformation of hippocampal neuronal representations in 'morphed' environments. Neuron 48, 345–358 (2005).

    Article  CAS  Google Scholar 

  29. Ruth, R.E., Collier, T.J. & Routtenberg, A. Topographical relationship between the entorhinal cortex and the septotemporal axis of the dentate gyrus in rats. II. Cells projecting from lateral entorhinal subdivisions. J. Comp. Neurol. 270, 506–516 (1988).

    Article  CAS  Google Scholar 

  30. Wills, T.J., Lever, C., Cacucci, F., Burgess, N. & O'Keefe, J. Attractor dynamics in the hippocampal representation of the local environment. Science 308, 873–876 (2005).

    Article  CAS  Google Scholar 

  31. Rolls, E.T., Stringer, S.M. & Ellio, T. Entorhinal cortex grid cells can map to hippocampal place cells by competitive learning. Network 17, 447–465 (2006).

    Article  Google Scholar 

  32. Savelli, F. & Knierim, J.J. Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields. J. Neurophysiol. 103, 3167–3183 (2010).

    Article  Google Scholar 

  33. Zhang, S.-J. et al. Optogenetric dissection of entorhinal-hippocampal functional connectivity. Science 340, 1232627 (2013).

    Article  Google Scholar 

  34. Köhler, C. Intrinsic projections of the retrohippocampal region in the rat brain. I. The subicular complex. J. Comp. Neurol. 236, 504–522 (1985).

    Article  Google Scholar 

  35. Boccara, C.N. et al. Grid cells in pre- and parasubiculum. Nat. Neurosci. 13, 987–994 (2010).

    Article  CAS  Google Scholar 

  36. McHugh, T.J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  Google Scholar 

  37. Buckner, R.L. & Wheeler, M.E. The cognitive neuroscience of remembering. Nat. Rev. Neurosci. 2, 624–634 (2001).

    Article  CAS  Google Scholar 

  38. Navawongse, R. & Eichenbaum, H. Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons. J. Neurosci. 33, 1002–1013 (2013).

    Article  CAS  Google Scholar 

  39. Vertes, R.P., Hoover, W.B., Szigeti-Buck, K. & Leranth, C. Nucleus reuniens of the midline thalamus: link between the medial prefrontal cortex and the hippocampus. Brain Res. Bull. 71, 601–609 (2007).

    Article  Google Scholar 

  40. Xu, W. & Südhof, T.C. A neural circuit for memory specificity and generalization. Science 339, 1290–1295 (2013).

    Article  CAS  Google Scholar 

  41. Ito, H.T., Witter, M.P., Moser, E.I. & Moser, M.-B. Representation of behavioral context in the nucleus reuniens for CA1 place cells. Soc. Neurosci. Abstr. 702.04 (2013).

  42. Room, P., Russchen, F.T., Groenewegen, H.J. & Lohman, A.H. Efferent connections of the prelimbic (area 32) and the infralimbic (area 25) cortices: an anterograde tracing study in the cat. J. Comp. Neurol. 242, 40–55 (1985).

    Article  CAS  Google Scholar 

  43. Burwell, R.D. & Amaral, D.G. Cortical afferents of the perirhinal, postrhinal, and entorhinal cortices of the rat. J. Comp. Neurol. 398, 179–205 (1998).

    Article  CAS  Google Scholar 

  44. Dolorfo, C.L. & Amaral, D.G. Entorhinal cortex of the rat: organization of intrinsic connections. J. Comp. Neurol. 398, 49–82 (1998).

    Article  CAS  Google Scholar 

  45. Eichenbaum, H. A cortical-hippocampal system for declarative memory. Nat. Rev. Neurosci. 1, 41–50 (2000).

    Article  CAS  Google Scholar 

  46. Rennó-Costa, C., Lisman, J.E. & Verschure, P.F. The mechanism of rate remapping in the dentate gyrus. Neuron 68, 1051–1058 (2010).

    Article  Google Scholar 

  47. Fenton, A.A. & Muller, R.U. Place cell discharge is extremely variable during individual passes of the rat through the firing field. Proc. Natl. Acad. Sci. USA 95, 3182–3187 (1998).

    Article  CAS  Google Scholar 

  48. Kentros, C.G., Agnihotri, N.T., Streater, S., Hawkins, R.D. & Kandel, E.R. Increased attention to spatial context increases both place field stability and spatial memory. Neuron 42, 283–295 (2004).

    Article  CAS  Google Scholar 

  49. Jezek, K., Henriksen, E.J., Treves, A., Moser, E.I. & Moser, M.-B. Theta-paced flickering between place-cell maps in the hippocampus. Nature 478, 246–249 (2011).

    Article  CAS  Google Scholar 

  50. Blumenfeld, B., Preminger, S., Sagi, D. & Tsodyks, M. Dynamics of memory representations in networks with novelty-facilitated synaptic plasticity. Neuron 52, 383–394 (2006).

    Article  CAS  Google Scholar 

  51. Skaggs, W.E., McNaughton, B.L., Wilson, M.A. & Barnes, C.A. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus 6, 149–172 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A.M. Amundgård, K. Haugen, K. Jenssen, E. Kråkvik, R. Skjerpeng and H. Waade for technical assistance. This work was supported by the Kavli Foundation and a Centre of Excellence grant from the Research Council of Norway.

Author information

Authors and Affiliations

Authors

Contributions

J.K.L., S.L., E.I.M. and M.-B.M. conceived and designed the experiment. E.J.H. made lesions. S.L., L.L. and E.J.H. implanted hippocampal tetrodes. J.K.L., L.L. and E.J.H. performed the hippocampal recording experiments. J.K.L., L.L. and S.L. analyzed the hippocampal data. A.T. implanted LEC tetrodes and recorded and analyzed LEC cells. L.L. made figures. L.L., E.J.H. and M.P.W. evaluated lesions and made unfolded maps. A.T., E.J.H., L.L. and M.P.W. determined LEC recording locations. M.P.W. carried out tracing experiments and analyses. E.I.M. and L.L. wrote the manuscript. M.-B.M. and E.I.M. supervised and coordinated the project. All of the authors contributed to discussion and interpretation.

Corresponding authors

Correspondence to Li Lu, Jill K Leutgeb or Edvard I Moser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Text

Supplementary Figures 1-11 and Supplementary Table 1 (PDF 22233 kb)

Supplementary Table 2

Source data for supplementary figures. (XLS 687 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, L., Leutgeb, J., Tsao, A. et al. Impaired hippocampal rate coding after lesions of the lateral entorhinal cortex. Nat Neurosci 16, 1085–1093 (2013). https://doi.org/10.1038/nn.3462

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3462

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing