Spatiotemporally random and diverse grid cell spike patterns contribute to the transformation of grid cell to place cell in a neural network model

Autoři: Sahn Woo Park aff001;  Hyun Jae Jang aff001;  Mincheol Kim aff001;  Jeehyun Kwag aff001
Působiště autorů: Neural Computational Laboratory, Department of Brain and Cognitive Engineering, Korea University, Seoul, Korea aff001
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225100


The medial entorhinal cortex and the hippocampus are brain regions specialized in spatial information processing. While an animal navigates around an environment, grid cells in the medial entorhinal cortex spike at multiple discrete locations, forming hexagonal grid patterns, and each grid cell is spatiotemporally dynamic with a different grid size, spacing, and orientation. In contrast, place cells in the hippocampus spike when an animal is at one or more specific locations, called a “place field”. While an animal traverses through a place field, the place cell’s spike phases relative to the hippocampal theta-frequency oscillation advance in phase, known as the “spike phase precession” phenomenon and each spike encodes the specific location within the place field. Interestingly, the medial entorhinal cortical grid cells and the hippocampal place cells are only one excitatory synapse apart. However, how the spatiotemporally dynamic multi-peaked grid cell activities are transformed into hippocampal place cell activities with spike phase precession phenomenon is yet unknown. To address this question, we construct an anatomically and physiologically realistic neural network model comprised of 10,000 grid cell models, each with a spatiotemporally dynamic grid patterns and a place cell model connected by excitatory synapses. Using this neural network model, we show that grid cells’ spike activities with spatiotemporally random and diverse grid orientation, spacing, and phases as inputs to place cell are able to generate a place field with spike phase precession. These results indicate that spatiotemporally random and diverse grid cell spike activities are essential for the formation of place cell activity observed in vivo.

Klíčová slova:

Action potentials – Cell physiology – Hippocampus – Neural networks – Neuronal dendrites – Synapses – Precession – Cell transformation


1. Hafting T, Fyhn M, Molden S, Moser MB, Moser EI. Microstructure of a spatial map in the entorhinal cortex. Nature. 2005;436(7052):801–6. Epub 2005/06/21. doi: 10.1038/nature03721 15965463.

2. Fyhn M, Molden S, Witter MP, Moser EI, Moser MB. Spatial representation in the entorhinal cortex. Science. 2004;305(5688):1258–64. doi: 10.1126/science.1099901 15333832.

3. Sargolini F, Fyhn M, Hafting T, McNaughton BL, Witter MP, Moser MB, et al. Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science. 2006;312(5774):758–62. doi: 10.1126/science.1125572 16675704.

4. O'Keefe J, Burgess N. Geometric determinants of the place fields of hippocampal neurons. Nature. 1996;381(6581):425–8. Epub 1996/05/30. doi: 10.1038/381425a0 8632799.

5. O'Keefe J, Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain research. 1971;34(1):171–5. doi: 10.1016/0006-8993(71)90358-1 5124915.

6. O'Keefe J, Recce ML. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus. 1993;3(3):317–30. Epub 1993/07/01. doi: 10.1002/hipo.450030307 8353611.

7. Fyhn M, Hafting T, Treves A, Moser MB, Moser EI. Hippocampal remapping and grid realignment in entorhinal cortex. Nature. 2007;446(7132):190–4. Epub 2007/02/27. doi: 10.1038/nature05601 17322902.

8. Brun VH, Solstad T, Kjelstrup KB, Fyhn M, Witter MP, Moser EI, et al. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus. 2008;18(12):1200–12. Epub 2008/11/21. doi: 10.1002/hipo.20504 19021257.

9. Moser EI, Roudi Y, Witter MP, Kentros C, Bonhoeffer T, Moser MB. Grid cells and cortical representation. Nat Rev Neurosci. 2014;15(7):466–81. doi: 10.1038/nrn3766 24917300.

10. Stensola H, Stensola T, Solstad T, Froland K, Moser MB, Moser EI. The entorhinal grid map is discretized. Nature. 2012;492(7427):72–8. doi: 10.1038/nature11649 23222610.

11. Fenton AA, Kao HY, Neymotin SA, Olypher A, Vayntrub Y, Lytton WW, et al. Unmasking the CA1 ensemble place code by exposures to small and large environments: more place cells and multiple, irregularly arranged, and expanded place fields in the larger space. J Neurosci. 2008;28(44):11250–62. Epub 2008/10/31. doi: 10.1523/JNEUROSCI.2862-08.2008 18971467; PubMed Central PMCID: PMC2695947.

12. Park E, Dvorak D, Fenton AA. Ensemble place codes in hippocampus: CA1, CA3, and dentate gyrus place cells have multiple place fields in large environments. PLoS One. 2011;6(7):e22349. Epub 2011/07/27. doi: 10.1371/journal.pone.0022349 21789250; PubMed Central PMCID: PMC3137630.

13. Skaggs WE, McNaughton BL, Wilson MA, Barnes CA. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus. 1996;6(2):149–72. Epub 1996/01/01. doi: 10.1002/(SICI)1098-1063(1996)6:2<149::AID-HIPO6>3.0.CO;2-K 8797016.

14. Amaral DG, Witter MP. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience. 1989;31(3):571–91. doi: 10.1016/0306-4522(89)90424-7 2687721.

15. de Almeida L, Idiart M, Lisman JE. The input-output transformation of the hippocampal granule cells: from grid cells to place fields. J Neurosci. 2009;29(23):7504–12. doi: 10.1523/JNEUROSCI.6048-08.2009 19515918; PubMed Central PMCID: PMC2747669.

16. Solstad T, Moser EI, Einevoll GT. From grid cells to place cells: a mathematical model. Hippocampus. 2006;16(12):1026–31. Epub 2006/11/10. doi: 10.1002/hipo.20244 17094145.

17. Schlesiger MI, Cannova CC, Boublil BL, Hales JB, Mankin EA, Brandon MP, et al. The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity. Nat Neurosci. 2015;18(8):1123–32. Epub 2015/06/30. doi: 10.1038/nn.4056 26120964; PubMed Central PMCID: PMC4711275.

18. Hales JB, Schlesiger MI, Leutgeb JK, Squire LR, Leutgeb S, Clark RE. Medial entorhinal cortex lesions only partially disrupt hippocampal place cells and hippocampus-dependent place memory. Cell Rep. 2014;9(3):893–901. doi: 10.1016/j.celrep.2014.10.009 25437546; PubMed Central PMCID: PMC4294707.

19. Van Cauter T, Poucet B, Save E. Unstable CA1 place cell representation in rats with entorhinal cortex lesions. Eur J Neurosci. 2008;27(8):1933–46. doi: 10.1111/j.1460-9568.2008.06158.x 18412614.

20. Zhang SJ, Ye J, Miao C, Tsao A, Cerniauskas I, Ledergerber D, et al. Optogenetic dissection of entorhinal-hippocampal functional connectivity. Science. 2013;340(6128):1232627. doi: 10.1126/science.1232627 23559255.

21. Zhao R, Grunke SD, Keralapurath MM, Yetman MJ, Lam A, Lee TC, et al. Impaired Recall of Positional Memory following Chemogenetic Disruption of Place Field Stability. Cell Rep. 2016;16(3):793–804. doi: 10.1016/j.celrep.2016.06.032 27373150; PubMed Central PMCID: PMC4956499.

22. Amaral DG, Ishizuka N, Claiborne B. Neurons, numbers and the hippocampal network. Progress in brain research. 1990;83:1–11. doi: 10.1016/s0079-6123(08)61237-6 2203093.

23. Molter C, Yamaguchi Y. Impact of temporal coding of presynaptic entorhinal cortex grid cells on the formation of hippocampal place fields. Neural networks: the official journal of the International Neural Network Society. 2008;21(2–3):303–10. doi: 10.1016/j.neunet.2007.12.032 18242058.

24. Si B, Treves A. The role of competitive learning in the generation of DG fields from EC inputs. Cognitive neurodynamics. 2009;3(2):177–87. doi: 10.1007/s11571-009-9079-z 19301148; PubMed Central PMCID: PMC2678203.

25. Azizi AH, Schieferstein N, Cheng S. The transformation from grid cells to place cells is robust to noise in the grid pattern. Hippocampus. 2014;24(8):912–9. doi: 10.1002/hipo.22306 24866281.

26. Jaramillo J, Schmidt R, Kempter R. Modeling inheritance of phase precession in the hippocampal formation. J Neurosci. 2014;34(22):7715–31. doi: 10.1523/JNEUROSCI.5136-13.2014 24872575.

27. Rolls ET, Stringer SM, Elliot T. Entorhinal cortex grid cells can map to hippocampal place cells by competitive learning. Network-Comp Neural. 2006;17(4):447–65. doi: 10.1080/09548980601064846 PubMed PMID: 000244139800006. 17162463

28. Lyttle D, Gereke B, Lin KK, Fellous JM. Spatial scale and place field stability in a grid-to-place cell model of the dorsoventral axis of the hippocampus. Hippocampus. 2013;23(8):729–44. Epub 2013/04/12. doi: 10.1002/hipo.22132 23576417; PubMed Central PMCID: PMC4120775.

29. Hayman RM, Jeffery KJ. How Heterogeneous Place Cell Responding Arises From Homogeneous Grids-A Contextual Gating Hypothesis. Hippocampus. 2008;18(12):1301–13. doi: 10.1002/hipo.20513 PubMed PMID: 000261871800013. 19021264

30. Savelli F, Knierim JJ. Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields. Journal of neurophysiology. 2010;103(6):3167–83. doi: 10.1152/jn.00932.2009 20357069; PubMed Central PMCID: PMC2888241.

31. Harvey CD, Collman F, Dombeck DA, Tank DW. Intracellular dynamics of hippocampal place cells during virtual navigation. Nature. 2009;461(7266):941–6. Epub 2009/10/16. doi: 10.1038/nature08499 19829374; PubMed Central PMCID: PMC2771429.

32. Kamondi A, Acsady L, Wang XJ, Buzsaki G. Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: activity-dependent phase-precession of action potentials. Hippocampus. 1998;8(3):244–61. doi: 10.1002/(SICI)1098-1063(1998)8:3<244::AID-HIPO7>3.0.CO;2-J 9662139.

33. Kwag J, Jang HJ, Kim M, Lee S. M-type potassium conductance controls the emergence of neural phase codes: a combined experimental and neuron modelling study. J R Soc Interface. 2014;11(99). Epub 2014/08/08. doi: 10.1098/rsif.2014.0604 25100320; PubMed Central PMCID: PMC4233740.

34. Magee JC. Dendritic mechanisms of phase precession in hippocampal CA1 pyramidal neurons. Journal of neurophysiology. 2001;86(1):528–32. Epub 2001/06/30. doi: 10.1152/jn.2001.86.1.528 11431530.

35. Hayman RM, Jeffery KJ. How heterogeneous place cell responding arises from homogeneous grids—a contextual gating hypothesis. Hippocampus. 2008;18(12):1301–13. doi: 10.1002/hipo.20513 19021264.

36. Rapp PR, Deroche PS, Mao Y, Burwell RD. Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits. Cereb Cortex. 2002;12(11):1171–9. doi: 10.1093/cercor/12.11.1171 12379605.

37. Ishizuka N, Cowan WM, Amaral DG. A quantitative analysis of the dendritic organization of pyramidal cells in the rat hippocampus. J Comp Neurol. 1995;362(1):17–45. doi: 10.1002/cne.903620103 8576427.

38. Burgess N, Barry C, O'Keefe J. An oscillatory interference model of grid cell firing. Hippocampus. 2007;17(9):801–12. Epub 2007/06/29. doi: 10.1002/hipo.20327 17598147; PubMed Central PMCID: PMC2678278.

39. Hasselmo ME. Grid cell mechanisms and function: contributions of entorhinal persistent spiking and phase resetting. Hippocampus. 2008;18(12):1213–29. doi: 10.1002/hipo.20512 19021258; PubMed Central PMCID: PMC2614862.

40. Zilli EA, Yoshida M, Tahvildari B, Giocomo LM, Hasselmo ME. Evaluation of the oscillatory interference model of grid cell firing through analysis and measured period variance of some biological oscillators. PLoS computational biology. 2009;5(11):e1000573. doi: 10.1371/journal.pcbi.1000573 19936051; PubMed Central PMCID: PMC2773844.

41. Shah MM, Migliore M, Brown DA. Differential effects of Kv7 (M-) channels on synaptic integration in distinct subcellular compartments of rat hippocampal pyramidal neurons. J Physiol. 2011;589(Pt 24):6029–38. doi: 10.1113/jphysiol.2011.220913 22041186; PubMed Central PMCID: PMC3245855.

42. Chapman CA, Lacaille JC. Cholinergic induction of theta-frequency oscillations in hippocampal inhibitory interneurons and pacing of pyramidal cell firing. J Neurosci. 1999;19(19):8637–45. doi: 10.1523/JNEUROSCI.19-19-08637.1999 10493764.

43. Cobb SR, Buhl EH, Halasy K, Paulsen O, Somogyi P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature. 1995;378(6552):75–8. doi: 10.1038/378075a0 7477292.

44. Dragoi G. Internal operations in the hippocampus: single cell and ensemble temporal coding. Front Syst Neurosci. 2013;7:46. Epub 2013/09/07. doi: 10.3389/fnsys.2013.00046 24009564; PubMed Central PMCID: PMC3756298.

45. Huxter JR, Senior TJ, Allen K, Csicsvari J. Theta phase-specific codes for two-dimensional position, trajectory and heading in the hippocampus. Nat Neurosci. 2008;11(5):587–94. Epub 2008/04/22. doi: 10.1038/nn.2106 18425124.

46. Buzsaki G. Theta oscillations in the hippocampus. Neuron. 2002;33(3):325–40. Epub 2002/02/08. doi: 10.1016/s0896-6273(02)00586-x 11832222.

47. Tropp J, Figueiredo CM, Markus EJ. Stability of hippocampal place cell activity across the rat estrous cycle. Hippocampus. 2005;15(2):154–65. doi: 10.1002/hipo.20042 15390155.

48. Magee JC, Cook EP. Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Nat Neurosci. 2000;3(9):895–903. doi: 10.1038/78800 10966620.

49. Sterratt DC, Groen MR, Meredith RM, van Ooyen A. Spine calcium transients induced by synaptically-evoked action potentials can predict synapse location and establish synaptic democracy. PLoS computational biology. 2012;8(6):e1002545. Epub 2012/06/22. doi: 10.1371/journal.pcbi.1002545 22719238; PubMed Central PMCID: PMC3375220.

50. Otmakhova NA, Otmakhov N, Lisman JE. Pathway-specific properties of AMPA and NMDA-mediated transmission in CA1 hippocampal pyramidal cells. J Neurosci. 2002;22(4):1199–207. Epub 2002/02/19. doi: 10.1523/JNEUROSCI.22-04-01199.2002 11850447.

51. Zhang S, Schonfeld F, Wiskott L, Manahan-Vaughan D. Spatial representations of place cells in darkness are supported by path integration and border information. Front Behav Neurosci. 2014;8:222. Epub 2014/07/11. doi: 10.3389/fnbeh.2014.00222 25009477; PubMed Central PMCID: PMC4068307.

52. Hussaini SA, Kempadoo KA, Thuault SJ, Siegelbaum SA, Kandel ER. Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. Neuron. 2011;72(4):643–53. Epub 2011/11/22. doi: 10.1016/j.neuron.2011.09.007 22099465; PubMed Central PMCID: PMC4435580.

53. Castro L, Aguiar P. A feedforward model for the formation of a grid field where spatial information is provided solely from place cells. Biol Cybern. 2014;108(2):133–43. Epub 2014/03/01. doi: 10.1007/s00422-013-0581-3 24577877.

54. Hollup SA, Molden S, Donnett JG, Moser MB, Moser EI. Accumulation of hippocampal place fields at the goal location in an annular watermaze task. J Neurosci. 2001;21(5):1635–44. doi: 10.1523/JNEUROSCI.21-05-01635.2001 11222654.

55. Huxter J, Burgess N, O'Keefe J. Independent rate and temporal coding in hippocampal pyramidal cells. Nature. 2003;425(6960):828–32. doi: 10.1038/nature02058 14574410; PubMed Central PMCID: PMC2677642.

56. De Boor C, De Boor C, Mathématicien E-U, De Boor C, De Boor C. A practical guide to splines: Springer-Verlag New York; 1978.

57. Hines ML, Carnevale NT. The NEURON simulation environment. Neural Comput. 1997;9(6):1179–209. Epub 1997/08/15. doi: 10.1162/neco.1997.9.6.1179 9248061.

58. Miao C, Cao Q, Ito HT, Yamahachi H, Witter MP, Moser MB, et al. Hippocampal Remapping after Partial Inactivation of the Medial Entorhinal Cortex. Neuron. 2015;88(3):590–603. Epub 2015/11/06. doi: 10.1016/j.neuron.2015.09.051 26539894.

59. Kanter BR, Lykken CM, Avesar D, Weible A, Dickinson J, Dunn B, et al. A Novel Mechanism for the Grid-to-Place Cell Transformation Revealed by Transgenic Depolarization of Medial Entorhinal Cortex Layer II. Neuron. 2017;93(6):1480–92 e6. doi: 10.1016/j.neuron.2017.03.001 28334610.

60. Rueckemann JW, DiMauro AJ, Rangel LM, Han X, Boyden ES, Eichenbaum H. Transient optogenetic inactivation of the medial entorhinal cortex biases the active population of hippocampal neurons. Hippocampus. 2016;26(2):246–60. Epub 2015/08/25. doi: 10.1002/hipo.22519 26299904; PubMed Central PMCID: PMC4718858.

61. Mehta MR, Lee AK, Wilson MA. Role of experience and oscillations in transforming a rate code into a temporal code. Nature. 2002;417(6890):741–6. Epub 2002/06/18. doi: 10.1038/nature00807 12066185.

62. Masurkar AV, Srinivas KV, Brann DH, Warren R, Lowes DC, Siegelbaum SA. Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons. Cell Rep. 2017;18(1):148–60. Epub 2017/01/05. doi: 10.1016/j.celrep.2016.12.012 28052245; PubMed Central PMCID: PMC5381513.

63. Otmakhova NA, Lewey J, Asrican B, Lisman JE. Inhibition of perforant path input to the CA1 region by serotonin and noradrenaline. Journal of neurophysiology. 2005;94(2):1413–22. Epub 2005/05/13. doi: 10.1152/jn.00217.2005 15888529.

64. Yamaguchi Y, Aota Y, McNaughton BL, Lipa P. Bimodality of theta phase precession in hippocampal place cells in freely running rats. Journal of neurophysiology. 2002;87(6):2629–42. Epub 2002/05/31. doi: 10.1152/jn.2002.87.6.2629 12037166.

65. Fernandez-Ruiz A, Oliva A, Nagy GA, Maurer AP, Berenyi A, Buzsaki G. Entorhinal-CA3 Dual-Input Control of Spike Timing in the Hippocampus by Theta-Gamma Coupling. Neuron. 2017;93(5):1213–26 e5. Epub 2017/03/11. doi: 10.1016/j.neuron.2017.02.017 28279355; PubMed Central PMCID: PMC5373668.

66. Rall W. Theory of physiological properties of dendrites. Ann N Y Acad Sci. 1962;96:1071–92. doi: 10.1111/j.1749-6632.1962.tb54120.x 14490041.

67. Johnston D, Magee JC, Colbert CM, Cristie BR. Active properties of neuronal dendrites. Annu Rev Neurosci. 1996;19:165–86. doi: 10.1146/ 8833440.

68. Magee JC. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J Neurosci. 1998;18(19):7613–24. doi: 10.1523/JNEUROSCI.18-19-07613.1998 9742133.

69. Kjelstrup KB, Solstad T, Brun VH, Hafting T, Leutgeb S, Witter MP, et al. Finite scale of spatial representation in the hippocampus. Science. 2008;321(5885):140–3. Epub 2008/07/05. doi: 10.1126/science.1157086 18599792.

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