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.

Spontaneous persistent activity in entorhinal cortex modulates cortico-hippocampal interaction in vivo

Abstract

Persistent activity is thought to mediate working memory during behavior. Can it also occur during sleep? We found that the membrane potential of medial entorhinal cortex layer III (MECIII) neurons, a gateway between neocortex and hippocampus, showed spontaneous, stochastic persistent activity in vivo in mice during Up-Down state oscillations (UDS). This persistent activity was locked to the neocortical Up states with a short delay, but persisted over several cortical UDS cycles. Lateral entorhinal neurons did not show substantial persistence, and current injections similar to those used in vitro failed to elicit persistence in vivo, implicating network mechanisms. Hippocampal CA1 neurons' spiking activity was reduced during neocortical Up states, but was increased during MECIII persistent states. These results provide, to the best of our knowledge, the first direct evidence for persistent activity in MECIII neurons in vivo and reveal its contribution to cortico-hippocampal interaction that could be involved in working memory and learning of long behavioral sequences during behavior, and memory consolidation during sleep.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Spontaneous persistent activity in MECIII, but not LECIII, neurons.
Figure 2: Differential delays of MECIII Up and Down transitions relative to neocortical UDS.
Figure 3: Quantization of MECIII persistent Up state durations in units of neocortical UDS.
Figure 4: Examples of MECIII persistent Up states during natural sleep.
Figure 5: Differential influence of neocortical and MECIII UDS on CA1 activity.
Figure 6: Temporal relationship of MECIII persistent Up states and CA1 activity.
Figure 7: Stochastic mechanism for MECIII persistent Up states and their influence on cortico-entorhinal-hippocampal responses during UDS oscillations.

References

  1. 1

    Steriade, M., Nuñez, A. & Amzica, F. A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J. Neurosci. 13, 3252–3265 (1993).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Destexhe, A., Contreras, D. & Steriade, M. Spatiotemporal analysis of local field potentials and unit discharges in cat cerebral cortex during natural wake and sleep states. J. Neurosci. 19, 4595–4608 (1999).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Petersen, C.C.H., Hahn, T.T.G., Mehta, M., Grinvald, A. & Sakmann, B. Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex. Proc. Natl. Acad. Sci. USA 100, 13638–13643 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Clement, E.A. et al. Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia. PLoS ONE 3, e2004 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5

    Sirota, A., Csicsvari, J., Buhl, D. & Buzsáki, G. Communication between neocortex and hippocampus during sleep in rodents. Proc. Natl. Acad. Sci. USA 100, 2065–2069 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Hahn, T.T.G., Sakmann, B. & Mehta, M.R. Phase-locking of hippocampal interneurons' membrane potential to neocortical up-down states. Nat. Neurosci. 9, 1359–1361 (2006).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Hahn, T.T.G., Sakmann, B. & Mehta, M.R. Differential responses of hippocampal subfields to cortical up-down states. Proc. Natl. Acad. Sci. USA 104, 5169–5174 (2007).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Isomura, Y. et al. Integration and segregation of activity in entorhinal-hippocampal subregions by neocortical slow oscillations. Neuron 52, 871–882 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Ji, D. & Wilson, M.A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat. Neurosci. 10, 100–107 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Marr, D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 262, 23–81 (1971).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Squire, L.R. Memory and the hippocampus: a synthesis from findings with rats, monkeys and humans. Psychol. Rev. 99, 195–231 (1992).

    CAS  Article  Google Scholar 

  12. 12

    McClelland, J.L. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev. 102, 419–457 (1995).

    Article  Google Scholar 

  13. 13

    Remondes, M. & Schuman, E.M. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature 431, 699–703 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Marshall, L., Helgadóttir, H., Mölle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Diekelmann, S. & Born, J. The memory function of sleep. Nat. Rev. Neurosci. 11, 114–126 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Suh, J., Rivest, A.J., Nakashiba, T., Tominaga, T. & Tonegawa, S. Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory. Science 334, 1415–1420 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Oxford University Press, 1979).

  18. 18

    Wolansky, T., Clement, E.A., Peters, S.R., Palczak, M.A. & Dickson, C.T. Hippocampal slow oscillation: a novel EEG state and its coordination with ongoing neocortical activity. J. Neurosci. 26, 6213–6229 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Witter, M.P. Organization of the entorhinal-hippocampal system: a review of current anatomical data. Hippocampus 3, 33–44 (1993).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    van Strien, N.M., Cappaert, N.L.M. & Witter, M.P. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat. Rev. Neurosci. 10, 272–282 (2009).

    CAS  Article  Google Scholar 

  21. 21

    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  PubMed Central  Article  Google Scholar 

  22. 22

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

    Manns, J.R. & Eichenbaum, H. Evolution of declarative memory. Hippocampus 16, 795–808 (2006).

    PubMed  Article  Google Scholar 

  25. 25

    Knierim, J.J. Neural representations of location outside the hippocampus. Learn. Mem. 13, 405–415 (2006).

    PubMed  Article  Google Scholar 

  26. 26

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

    Google Scholar 

  27. 27

    Brun, V.H. et al. Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron 57, 290–302 (2008).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Egorov, A.V., Hamam, B., Fransén, E., Hasselmo, M. & Alonso, A. Graded persistent activity in entorhinal cortex neurons. Nature 420, 173–178 (2002).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Tahvildari, B., Fransén, E., Alonso, A.A. & Hasselmo, M.E. Switching between “On” and “Off” states of persistent activity in lateral entorhinal layer III neurons. Hippocampus 17, 257–263 (2007).

    PubMed  Article  Google Scholar 

  30. 30

    Yoshida, M., Fransén, E. & Hasselmo, M.E. mGluR-dependent persistent firing in entorhinal cortex layer III neurons. Eur. J. Neurosci. 28, 1116–1126 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Volgushev, M., Chauvette, S., Mukovski, M. & Timofeev, I. Precise long-range synchronization of activity and silence in neocortical neurons during slow-wave oscillations. J. Neurosci. 26, 5665–5672 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Mann, E.O., Kohl, M.M. & Paulsen, O. Distinct roles of GABA(A) and GABA(B) receptors in balancing and terminating persistent cortical activity. J. Neurosci. 29, 7513–7518 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Canto, C.B. & Witter, M.P. Cellular properties of principal neurons in the rat entorhinal cortex. I. The lateral entorhinal cortex. Hippocampus 22, 1256–1276 (2012).

    PubMed  Article  Google Scholar 

  34. 34

    Canto, C.B. & Witter, M.P. Cellular properties of principal neurons in the rat entorhinal cortex. II. The medial entorhinal cortex. Hippocampus 22, 1277–1299 (2012).

    PubMed  Article  Google Scholar 

  35. 35

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Gloveli, T., Schmitz, D., Empson, R.M., Dugladze, T. & Heinemann, U. Morphological and electrophysiological characterization of layer III cells of the medial entorhinal cortex of the rat. Neuroscience 77, 629–648 (1997).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Tahvildari, B. & Alonso, A. Morphological and electrophysiological properties of lateral entorhinal cortex layers II and III principal neurons. J. Comp. Neurol. 491, 123–140 (2005).

    PubMed  Article  Google Scholar 

  38. 38

    Friedberg, M.H., Lee, S.M. & Ebner, F.F. Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia. J. Neurophysiol. 81, 2243–2252 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Steriade, M., Timofeev, I. & Grenier, F. Natural waking and sleep states: a view from inside neocortical neurons. J. Neurophysiol. 85, 1969–1985 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Fransén, E., Tahvildari, B., Egorov, A.V., Hasselmo, M.E. & Alonso, A.A. Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons. Neuron 49, 735–746 (2006).

    PubMed  Article  CAS  Google Scholar 

  41. 41

    Ahmed, O.J. & Mehta, M.R. The hippocampal rate code: anatomy, physiology and theory. Trends Neurosci. 32, 329–338 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Henriksen, E.J. et al. Spatial representation along the proximodistal axis of CA1. Neuron 68, 127–137 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Major, G. & Tank, D. Persistent neural activity: prevalence and mechanisms. Curr. Opin. Neurobiol. 14, 675–684 (2004).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Ghorbani, M., Mehta, M., Bruinsma, R. & Levine, A. Nonlinear-dynamics theory of up-down transitions in neocortical neural networks. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 85, 021908 (2012).

    PubMed  Article  CAS  Google Scholar 

  45. 45

    Mehta, M.R. Cortico-hippocampal interaction during up-down states and memory consolidation. Nat. Neurosci. 10, 13–15 (2007).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Goldman-Rakic, P.S. Cellular basis of working memory. Neuron 14, 477–485 (1995).

    CAS  Article  Google Scholar 

  47. 47

    Mehta, M.R., Barnes, C.A. & McNaughton, B.L. Experience-dependent, asymmetric expansion of hippocampal place fields. Proc. Natl. Acad. Sci. USA 94, 8918–8921 (1997).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Mehta, M.R., Quirk, M.C. & Wilson, M.A. Experience-dependent asymmetric shape of hippocampal receptive fields. Neuron 25, 707–715 (2000).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    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).

    CAS  Article  Google Scholar 

  50. 50

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Kasanetz, F., Riquelme, L.A. & Murer, M.G. Disruption of the two-state membrane potential of striatal neurones during cortical desynchronisation in anaesthetised rats. J. Physiol. (Lond.) 543, 577–589 (2002).

    CAS  Article  Google Scholar 

  52. 52

    Bokil, H., Andrews, P., Kulkarni, J.E., Mehta, S. & Mitra, P.P. Chronux: a platform for analyzing neural signals. J. Neurosci. Methods 192, 146–151 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Thomson, D.J. Spectrum estimation and harmonic analysis. Proc. IEEE 70, 1055–1096 (1982).

    Article  Google Scholar 

  54. 54

    McFarland, J.M., Hahn, T.T.G. & Mehta, M.R. Explicit-duration hidden Markov model inference of UP-DOWN states from continuous signals. PLoS ONE 6, e21606 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank T. Fucke for extensive support with experiments. J.M.M. and M.R.M. were supported by the Whitehall Foundation, a National Science Foundation career award and the W.M. Keck Foundation. T.T.G.H. and S.B. were supported by the German Ministry of Education and Research (BMBF grants 01GQ1007 and 01GQ1003B), and supported by the Max Planck Society and the group of A. Schäfer at the Max Planck Institute for Medical Research. All of the authors were supported by NIH-BMBF-CRCNS grant 5R01MH092925-02 to M.R.M.

Author information

Affiliations

Authors

Contributions

T.T.G.H., J.M.M. and M.R.M. designed the study, T.T.G.H. and S.B. performed the experiments, and J.M.M. performed the data analysis. M.R.M. participated in all aspects of the study. All of the authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to Mayank R Mehta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 5201 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hahn, T., McFarland, J., Berberich, S. et al. Spontaneous persistent activity in entorhinal cortex modulates cortico-hippocampal interaction in vivo. Nat Neurosci 15, 1531–1538 (2012). https://doi.org/10.1038/nn.3236

Download citation

Further reading

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