Rhythmic Activity in the Hippocampus and Entorhinal Cortex is Impaired in a Model of Kainate Neurotoxicity in Rats in Free Behavior

The hippocampus and medial entorhinal cortex (MEC) interact by means of bidirectional connections and play an important role in the processing, memorization, and reproduction of information. Data obtained in healthy animals show that the θ and γ oscillations are critical activities necessary for the interaction of the hippocampus and the MEC in signal processing. At the same time, these structures are among the most vulnerable parts of the brain to hyperactivation leading to excitotoxic damage and neuron death. In the present study toxicity was provoked by systemic administration of kainic acid (KA), inducing the development of status epilepticus. In control rats given physiological saline and rats given injections of KA, local field potentials were recorded simultaneously in hippocampal field CA1 and the MEC during exploratory behavior in an open field. A clearly apparent θ rhythm (4–10 Hz) was observed, along with a slow γ rhythm (25–50 Hz) and a fast γ rhythm (55–100 Hz) in the hippocampus and MEC of animals of both groups. Movement of control animals to the center of the open field was accompanied by an increase in the frequency of the θ rhythm and a decrease in the frequency of the fast γ rhythm in the hippocampus; the MEC showed a decrease in the power of the slow γ rhythm. This was not seen in rats given KA. This group also showed impairment to the phase-amplitude modulation of MEC activity by the hippocampal θ rhythm: changes in this modulation on movement of animals from the peripheral zones to the center of the open field were significantly less marked than in controls. There was also a significant increase in θ coherence between the hippocampus and MEC for all locations of the animal in the open field. Changes in the characteristics of rhythms in hippocampus-entorhinal interactions are potential biomarkers for impairments to the coding of spatial information and its retrieval from memory due to status epilepticus and often leading to the development of a convulsive focus in the temporal structures of the brain.

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References

  1. Axmacher, N., Henseler, M. M., Jensen, O., et al., “Cross-frequency coupling supports multi-item working memory in the human hippocampus,” Proc. Natl. Acad. Sci. USA, 107, 3228–3233 (2010).

    CAS  PubMed  Google Scholar 

  2. Bastos, A. M., Vezol, J., and Fries, P., “Communication through coherence with inter-areal delays,” Curr. Opin. Neurobiol., 31, 173–180 (2015).

    CAS  PubMed  Google Scholar 

  3. Belluscio, M. A., Mizuseki, K., Schmidt, R., et al., “Cross-frequency phase–phase coupling between theta and gamma oscillations in the hippocampus,” J. Neurosci., 32, 423–435 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Benchenane, K., Peyrache, A., Khamassi, M., et al., “Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning,” Neuron, 66, No. 6, 921–936 (2010).

    CAS  PubMed  Google Scholar 

  5. Betjemann, J. P. and Lowenstein, D. H., “Status epilepticus in adults,” Lancet Neurol., 14, No. 6, 615–624 (2015).

    PubMed  Google Scholar 

  6. Bland, B. H., “The physiology and pharmacology of hippocampal formation theta rhythms,” Prog. Neurobiol., 26, 1–54 (1986).

    CAS  PubMed  Google Scholar 

  7. Bouyer, J., Montaron, M., and Rougeul, A., “Fast fronto-parietal rhythms during combined focused attentive behaviour and immobility in cat: cortical and thalamic localizations,” Electroencephalogr. Clin. Neurophysiol., 51, 244–252 (1981).

    CAS  PubMed  Google Scholar 

  8. Bragin, A., Engel, J., Jr., Wilson, C. L., et al., “Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection,” Epilepsia, 40, 1210–1221 (1999).

    CAS  PubMed  Google Scholar 

  9. Bragin, A., Jandó, G., Nádasdy, Z., et al., “Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat,” J. Neurosci., 15, 47–60 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Brun, V. H., Otnass, M. K., Molden, S., et al., “Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry,” Science, 296, 2243–2246 (2002).

    CAS  PubMed  Google Scholar 

  11. Buzsáki, G. and Moser, E. I., “Memory, navigation and theta rhythm in the hippocampal-entorhinal system,” Nat. Neurosci., 16, 130–138 (2013).

    PubMed  PubMed Central  Google Scholar 

  12. Buzsáki, G. and Wang, X. J., “Mechanisms of gamma oscillations,” Annu. Rev. Neurosci., 35, 203–225 (2010).

    Google Scholar 

  13. Buzsáki, G., “Theta oscillations in the hippocampus,” Neuron, 33, 325–340 (2002).

    PubMed  Google Scholar 

  14. Buzsáki, G., Rhythms of the Brain, Oxford University Press, New York (2006).

    Google Scholar 

  15. Canolty, R. T. and Knight, R. T., “The functional role of cross-frequency coupling,” Trends Cogn. Sci., 14, 506–515 (2010).

    PubMed  PubMed Central  Google Scholar 

  16. Canolty, R. T., Edwards, E., Dalal, S. S., et al., “Oscillatory phase coupling coordinates anatomically dispersed functional cell assemblies,” Proc. Natl. Acad. Sci. USA, 107, No. 40, 17356–17361 (2010).

    CAS  PubMed  Google Scholar 

  17. Canolty, R., Edwards, E., Dalal, S., et al., “High gamma power is phaselocked to theta oscillations in human neocortex,” Science, 313, 1626–1628 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cavanagh, J. F., Cohen, M. X., and Allen, J. J., “Prelude to and resolution of an error: EEG phase synchrony reveals cognitive control dynamics during action monitoring,” J. Neurosci., 29, 98–105 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chauvière, L., Rafrafi, N., Thinus-Blanc, C., et al., “Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy,” J. Neurosci., 29, No. 17, 5402–5410 (2009).

    PubMed  PubMed Central  Google Scholar 

  20. Colgin, L. L. and Moser, E. I., “Gamma oscillations in the hippocampus,” Physiology (Bethesda), 25, 319–329 (2010).

    Google Scholar 

  21. Colgin, L. L., “Do slow and fast gamma rhythms correspond to distinct functional states in the hippocampal network?” Brain Res., 1621, 309–315. (2015a).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Colgin, L. L., “Mechanisms and functions of theta rhythms,” Annu. Rev. Neurosci., 36, 295–312 (2013).

    CAS  PubMed  Google Scholar 

  23. Colgin, L. L., “Rhythms of the hippocampal network,” Nat. Rev. Neurosci., 17, No. 4, 239–249 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Colgin, L. L., “Theta-gamma coupling in the entorhinal-hippocampal system,” Curr. Opin. Neurobiol., 31, 45–50 (2015b).

    CAS  PubMed  Google Scholar 

  25. Colgin, L. L., Denninger, T., Fyhn, M., et al., “Frequency of gamma oscillations routes flow of information in the hippocampus,” Nature, 462, No. 7271, 353–357 (2009).

    CAS  PubMed  Google Scholar 

  26. Dupont, S., Van de Moortele, P., Samson, S., et al., “Episodic memory in left temporal lobe epilepsy: a functional MRI study,” Brain, 123, 1722 (2000).

    PubMed  Google Scholar 

  27. Fell, J. and Axmacher, N., “The role of phase synchronization in memory processes,” Nat. Rev. Neurosci., 12, 105–118 (2011).

    CAS  PubMed  Google Scholar 

  28. Fell, J., Klave, P., Lehnert, K., et al., “Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling,” Nat. Neurosci., 4, 1259–1264 (2001).

    CAS  PubMed  Google Scholar 

  29. Fell, J., Ludowig, E., Rosburg, T., et al., “Phase-locking within human mediotemporal lobe predicts memory formation,” Neuroimage, 43, 410–419 (2008).

    PubMed  Google Scholar 

  30. Freund, T. F. and Buzsaki, G., “Interneurons of the hippocampus,” Hippocampus, 6, 347–470 (1996).

    CAS  PubMed  Google Scholar 

  31. Fries, P., “Neuronal gamma-band synchronization as a fundamental process in cortical computation,” Annu. Rev. Neurosci., 32, 209–224 (2009).0

  32. Froriep, U. P., Kumar, A., Cosandier-Rimélé, D., et al., “Altered theta coupling between medial entorhinal cortex and dentate gyrus in temporal lobe epilepsy,” Epilepsia, 53, 1937–1947 (2012).

    PubMed  Google Scholar 

  33. Green, J. D. and Arduini, A. A., “Hippocampal electrical activity in arousal,” J. Neurophysiol, 17, No. 6, 533–557 (1954).

    CAS  PubMed  Google Scholar 

  34. Gregoriou, G. G., Gotts, S. J., Zhou, H., and Desimone, R., “Highfrequency, long-range coupling between prefrontal and visual cortex during attention,” Science, 324, 1207–1210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hafting, T., Fyhn, M., Bonnevie, T., et al., “Hippocampus-independent phase precession in entorhinal grid cells,” Nature, 453, 1248–1252 (2008).

    CAS  PubMed  Google Scholar 

  36. Hafting, T., Fyhn, M., Molden, S., et al., “Microstructure of a spatial map in the entorhinal cortex,” Nature, 436, 801–806 (2005).

    CAS  PubMed  Google Scholar 

  37. Hasselmo, M. E. and Stern, C. E., “Theta rhythm and the encoding and retrieval of space and time,” Neuroimage, 85, No. Part 2, 656–666 (2014).

  38. Hellier, J. L., Patrylo, P. R., Buckmaster, P. S., et al., “Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy,” Epilepsy Res., 31, 73–84 (1998).

    CAS  PubMed  Google Scholar 

  39. Helmstaedter, C., “Effects of chronic epilepsy on declarative memory systems,” Prog. Brain Res., 135, 439–453 (2002).

    CAS  PubMed  Google Scholar 

  40. Hurtado, J. M., Rubchinsky, L. L., and Sigvardt, K. A., “Statistical method for detection of phase-locking episodes in neural oscillations,” J. Neurophysiol, 91, 1883–1898 (2004).

    PubMed  Google Scholar 

  41. Inostroza, M., Brotons-Mas, J. R., Laurent, F., et al., “Specific impairment of ‘what-where-when’ episodic-like memory in experimental models of temporal lobe epilepsy,” J. Neurosci., 33, 17749–17762 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jensen, O. and Lisman, J. E., “Hippocampal sequence-encoding driven by a cortical multi-item working memory buffer,” Trends Neurosci., 28, 67–72 (2005).

    CAS  PubMed  Google Scholar 

  43. Kemere, C., Carr, M. F., Karlsson, M. P., and Frank, L. M., “Rapid and continuous modulation of hippocampal network state during exploration of new places,” PLoS One, 8, e73114 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kloosterman, F., Van Haeften, T., Witter, M. P., and Lopes Da Silva, F. H., “Electrophysiological characterization of interlaminar entorhinal connections: an essential link for re-entrance in the hippocampal-entorhinal system,” Eur. J. Neurosci., 18, 3037–3052 (2003).

    PubMed  Google Scholar 

  45. Kuniishi, H., Ichisaka, S., Yamamoto, M., et al., “Early deprivation increases high-leaning behavior, a novel anxiety-like behavior, in the open field test in rats,” Neurosci. Res., 123, 27–35 (2017).

    PubMed  Google Scholar 

  46. Lega, B., Burke, J., Jacobs, J., and Kahana, M. J., “Slow-theta-to-gamma phase amplitude coupling in human hippocampus supports the formation of new episodic memories,” Cereb. Cortex, 26, 268–278 (2016).

    PubMed  Google Scholar 

  47. Lemesle, B., Planton, M., Pagès, B., and Pariente, J., “Accelerated long-term forgetting and autobiographical memory disorders in temporal lobe epilepsy: One entity or two?” Rev. Neurol. (Paris), 173, No. 7–8, 498–505 (2017).

    CAS  Google Scholar 

  48. Lin, D. Q., Cai, X. Y., Wang, C. H., et al., “Optimal concentration of necrostatin-1 for protecting against hippocampal neuronal damage in mice with status epilepticus,” Neural Regen. Res., 15, No. 5, 936–943 (2020).

    PubMed  Google Scholar 

  49. Livanov, M. N., Krylov V. Yu., Ostrjakova, T. V., and Shulgina, G. I., “Slow field potential oscillations as one of the basic mechanisms of integrative activity of neurons [proceedings],” Act. Nerv. Super. (Praha), 19, 43–44 (1977).

  50. Lothman, E. W., Bertram, E. H., Kapur, J., and Stringer, J. L., “Recurrent spontaneous hippocampal seizures in the rats as a chronic sequela to limbic status epilepticus,” Epilepsy Res., 6, 110–118 (1990).

    CAS  PubMed  Google Scholar 

  51. Malkov, A. E., Shubina, L. V., and Kitchigina, V. F., “Effects of endocannabinoid-related compounds on the activity of septal and hippocampal neurons in a model of kainic neurotoxicity: study ex vivo,” Opera Med. Physiol., 4, No. 1, 23–34 (2018).

    Google Scholar 

  52. Mazarati, A., Bragin, A., Baldwin, R., et al., “Epileptogenesis after selfsustaining status epilepticus,” Epilepsia, 43, Suppl. 5, 74–80 (2002).

    PubMed  Google Scholar 

  53. Montgomery, S. M., Sirota, A., and Buzsáki, G., “Theta and gamma coordination of hippocampal networks during waking and rapid eye movement sleep,” J. Neurosci., 28, 6731–6741 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Moser, E. I., Roudi, Y., Witter, M., et al., “Grid cells and cortical representation,” Nat. Rev. Neurosci., 15, 466–481 (2014).

    CAS  PubMed  Google Scholar 

  55. Nácher, V., Ledberg, A., Deco, G., and Romo, R., “Coherent delta-band oscillations between cortical areas correlate with decision making,” Proc. Natl. Acad. Sci. USA, 110, 15,085–15,090 (2013).

    Google Scholar 

  56. Newman, E. L., Gillet, S. N., Climer, J. R., and Hasselmo, M. E., “Cholinergic blockade reduces theta-gamma phase amplitude coupling and speed modulation of theta frequency consistent with behavioral effects on encoding,” J. Neurosci., 33, 19635–19646 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. O’Keefe, J. and Conway, D. H., “Hippocampal place units in the freely moving rat: why they fire where they fire,” Exp. Brain Res., 31, No. 4, 573–590. (1978).

    PubMed  Google Scholar 

  58. O’Keefe, J. and Recce, M. L., “Phase relationship between hippocampal place units and the EEG theta rhythm,” Hippocampus, 3, No. 3, 317–330 (1993).

    PubMed  Google Scholar 

  59. O’Keefe, J., “Place units in the hippocampus of the freely moving rat,” Exp. Neurol., 51, 78–109 (1976).

    PubMed  Google Scholar 

  60. Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, Academic Press, Sydney (1998).

    Google Scholar 

  61. Petsche, H. and Stumpf, C., “The origin of theta-rhythm in the rabbit hippocampus,” Wien. Klin. Wochenschr., 74, 696–700 (1962).

    CAS  PubMed  Google Scholar 

  62. Prut, L. and Belzung, C., “The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review,” Eur. J. Pharmacol., 463, No. 1–3, 3–33 (2003).

    CAS  PubMed  Google Scholar 

  63. Rodriguez, E., George, N., Lachaux, J. P., et al., “Perception’s shadow: long-distance synchronization of human brain activity,” Nature, 397, 430–433 (1999).

    CAS  PubMed  Google Scholar 

  64. Schomburg, E. W., Fernández-Ruiz, A., Mizuseki, K., et al., “Theta phase segregation of input-specific gamma patterns in entorhinal-hippocampal networks,” Neuron, 84, 470–485 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Siegel, M., Warden, M. R., and Mille, E. K., “Phase-dependent neuronal coding of objects in short-term memory,” Proc. Natl. Acad. Sci. USA, 106, 21341–21346 (2009).

    CAS  PubMed  Google Scholar 

  66. Steffenach, H. A., Sloviter, R. S., Mose, E. I., and Moser, M. B., “Impaired retention of spatial memory after transection of longitudinally oriented axons of hippocampal CA3 pyramidal cells,” Proc. Natl. Acad. Sci. USA, 99, 3194–3198 (2002).

    CAS  PubMed  Google Scholar 

  67. Steward, O., “Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat,” J. Comp. Neurol., 167, 285–314 (1976).

    CAS  PubMed  Google Scholar 

  68. Strogatz, S. H., Nonlinear Dynamics and Chaos: With Applications to Physics, Biology, Chemistry and Engineering, Perseus Books, Cambridge, MA (2003).

  69. Stumpf, C., Petsche, H., and Gogolak, G., “The significance of the rabbit’s septum as a relay station between the midbrain and the hippocampus. II. The differential influence of drugs upon both the septal cell firing pattern and the hippocampus theta activity,” Electroencephalogr. Clin. Neurophysiol., 14, 212–219 (1962).

    CAS  PubMed  Google Scholar 

  70. Sutherland, R. J., Whishaw, I. Q., and Kolb, B., “A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat,” Behav. Brain Res., 7, No. 2, 133–153 (1983).

    CAS  PubMed  Google Scholar 

  71. Tan, H. M., Wills, T. J., and Cacucci, F., “The development of spatial and memory circuits in the rat,” Wiley Interdisc. Rev. Cogn. Sci., 8, No. 3, (2017).

  72. Taube, J. S., Muller, R. U., and Ranck, J. B., “Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations,” J. Neurosci., 10, 36–447 (1990).

    Google Scholar 

  73. Tort, A. B. L., Komorowski, R. W., Manns, J. R., et al., “Theta-gamma coupling increases during the learning of item-context associations,” Proc. Natl. Acad. Sci. USA, 106, 20,942–20,947 (2009).

    Google Scholar 

  74. Tramoni-Negre, E., Lambert, I., Bartolomei, F., and Felician, O., “Longterm memory deficits in temporal lobe epilepsy,” Rev. Neurol. (Paris), 73, No. 7–8, 490–497 (2017).

    Google Scholar 

  75. Treves, A. and Rolls, E. T., “Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network,” Hippocampus, 2, 189–199 (1992).

    CAS  PubMed  Google Scholar 

  76. Vanderwolf, C., “Hippocampal electrical activity and voluntary movement in the rat,” Electroencephalogr. Clin. Neurophysiol., 26, 407–418 (1969).

    CAS  PubMed  Google Scholar 

  77. Vinogradova, O. S., “Expression, control, and probable functional significance of the neuronal theta-rhythm,” Prog. Neurobiol., 45, 523–583 (1995).

    CAS  PubMed  Google Scholar 

  78. Vinogradova, O. S., “Hippocampus as comparator: role of the two input and two output systems of the hippocampus in selection and registration of information,” Hippocampus, 11, 578–598 (2001).

    CAS  PubMed  Google Scholar 

  79. Vinogradova, O. S., Kitchigina, V. F., Kudina, T. A., and Kutyreva, E. V., “Oscillatory θ processes in neurons in the septohippocampal system and their modulation by stem structures,” Usp. Sovr. Biol., 120, 103–112 (2000).

    Google Scholar 

  80. Womelsdorf, T., Fries, P., Mitra, P. P., and Desimone, R., “Gamma-band synchronization in visual cortex predicts speed of change detection,” Nature, 439, 733–736 (2006).

    CAS  PubMed  Google Scholar 

  81. Wulff, P., Ponomarenko, A. A., Bartos, M., et al., “Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons,” Proc. Natl. Acad. Sci. USA, 106, 3561–3566 (2009).

    CAS  PubMed  Google Scholar 

  82. Zheng, C., Bieri, K. W., Hwaun, E., and Colgin, L. L., “Fast gamma rhythms in the hippocampus promote encoding of novel object-place pairings,” eNeuro, 3, No. 2, pii: ENEURO.0001-16.2016 (2016).

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Correspondence to A. E. Malkov.

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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 70, No. 3, pp. 394–410, May–June, 2020.

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Malkov, A.E., Shevkova, L.V., Latyshkova, A.A. et al. Rhythmic Activity in the Hippocampus and Entorhinal Cortex is Impaired in a Model of Kainate Neurotoxicity in Rats in Free Behavior. Neurosci Behav Physi 51, 73–84 (2021). https://doi.org/10.1007/s11055-020-01041-7

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Keywords

  • open field
  • free behavior
  • exploratory activity
  • hippocampus
  • medial entorhinal cortex
  • oscillation
  • θ rhythm
  • γ rhythm
  • phase-amplitude modulation
  • intrafrequency coherence
  • kainate neurotoxicity