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Hippocampal synaptic plasticity, spatial memory and anxiety

Abstract

Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both memory and anxiety.

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Figure 1: GluA1 is required for short-term, but not long-term spatial memory.
Figure 2: Impaired spatial reference memory on the radial maze but normal spatial reference memory in the open-field water maze in Grin1ΔDGCA1 mice.
Figure 3: Impaired spatial discrimination but normal non-spatial discrimination in the water maze in the Grin1ΔDGCA1 mice.
Figure 4: Distinct contributions of the dorsal and ventral hippocampus to behaviour.

References

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

    Google Scholar 

  2. Burgess, N., Maguire, E. A. & O'Keefe, J. The human hippocampus and spatial and episodic memory. Neuron 35, 625–641 (2002).

    CAS  PubMed  Google Scholar 

  3. Olton, D. S. & Samuelson, R. J. Remembrance of places passed — spatial memory in rats. J. Exp. Psychol. Anim. Behav. Process. 2, 97–116 (1976).

    Google Scholar 

  4. Morris, R. G., Garrud, P., Rawlins, J. N. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).

    CAS  PubMed  Google Scholar 

  5. Morris, R. G., Schenk, F., Tweedie, F. & Jarrard, L. E. Ibotenate lesions of hippocampus and/or subiculum: dissociating components of allocentric spatial learning. Eur. J. Neurosci. 2, 1016–1028 (1990).

    PubMed  Google Scholar 

  6. Rawlins, J. N. & Olton, D. S. The septo-hippocampal system and cognitive mapping. Behav. Brain Res. 5, 331–358 (1982).

    CAS  PubMed  Google Scholar 

  7. O'Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).

    CAS  PubMed  Google Scholar 

  8. Maguire, E. A. et al. Knowing where and getting there: a human navigation network. Science 280, 921–924 (1998).

    CAS  PubMed  Google Scholar 

  9. Maguire, E. A., Burgess, N. & O'Keefe, J. Human spatial navigation: cognitive maps, sexual dimorphism, and neural substrates. Curr. Opin. Neurobiol. 9, 171–177 (1999).

    CAS  PubMed  Google Scholar 

  10. Sanderson, D. J. et al. Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model. Learn. Mem. 16, 379–386 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sanderson, D. J. & Bannerman, D. M. The role of habituation in hippocampus-dependent spatial working memory tasks: evidence from GluA1 AMPA receptor subunit knockout mice. Hippocampus 22, 981–994 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. 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  Google Scholar 

  14. Taube, J. S., Muller, R. U. & Ranck, J. B. Jr. Head-direction cells recorded from the postsubiculum in freely moving rats. II. Effects of environmental manipulations. J. Neurosci. 10, 436–447 (1990).

    CAS  PubMed  Google Scholar 

  15. Taube, J. S., Muller, R. U. & Ranck, J. B. Jr. Head-direction cells recorded from the postsubiculum in freely moving rats. I. Description and quantitative analysis. J. Neurosci. 10, 420–435 (1990).

    CAS  PubMed  Google Scholar 

  16. Savelli, F., Yoganarasimha, D. & Knierim, J. J. Influence of boundary removal on the spatial representations of the medial entorhinal cortex. Hippocampus 18, 1270–1282 (2008).

    PubMed  PubMed Central  Google Scholar 

  17. Solstad, T., Boccara, C. N., Kropff, E., Moser, M. B. & Moser, E. I. Representation of geometric borders in the entorhinal cortex. Science 322, 1865–1868 (2008).

    CAS  PubMed  Google Scholar 

  18. Lever, C., Burton, S., Jeewajee, A., O'Keefe, J. & Burgess, N. Boundary vector cells in the subiculum of the hippocampal formation. J. Neurosci. 29, 9771–9777 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Eichenbaum, H., Stewart, C. & Morris, R. G. Hippocampal representation in place learning. J. Neurosci. 10, 3531–3542 (1990).

    CAS  PubMed  Google Scholar 

  20. Schmitt, W. B., Deacon, R. M., Seeburg, P. H., Rawlins, J. N. & Bannerman, D. M. A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-A-deficient mice. J. Neurosci. 23, 3953–3959 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hebb, D. O. The Organization of Behavior (John Wiley & Sons, 1949).

    Google Scholar 

  22. Hebb, D. O. Textbook of Psychology 3rd edn (W. B. Saunders Company, 1972).

    Google Scholar 

  23. Konorski, J. Conditioned Reflexes and Neuron Organization (Hefner, 1948).

    Google Scholar 

  24. Bliss, T. V. & Lømo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    CAS  PubMed  Google Scholar 

  26. Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000).

    CAS  PubMed  Google Scholar 

  27. Keith, J. R. & Rudy, J. W. Why NMDA receptor-dependent long-term potentiation may not be a mechanism of learning and memory: re-appraisal of the NMDA receptor blockade strategy. Psychobiology 18, 251–257 (1990).

    CAS  Google Scholar 

  28. Gallistel, C. R. & Matzel, L. D. The neuroscience of learning: beyond the hebbian synapse. Annu. Rev. Psychol. 64, 169–200 (2013).

    CAS  PubMed  Google Scholar 

  29. Shors, T. J. & Matzel, L. D. Long-term potentiation: what's learning got to do with it? Behav. Brain Sci. 20, 597–614 (1997).

    CAS  PubMed  Google Scholar 

  30. Bannerman, D. M., Rawlins, J. N. P. & Good, M. A. The drugs don't work—or do they? Pharmacological and transgenic studies of the contribution of NMDA and GluR-A-containing AMPA receptors to hippocampal-dependent memory. Psychopharmacology (Berl.) 188, 552–566 (2006).

    CAS  Google Scholar 

  31. Cain, D. P., Saucier, D., Hall, J., Hargreaves, E. L. & Boon, F. Detailed behavioral analysis of water maze acquisition under APV or CNQX: contribution of sensorimotor disturbances to drug-induced acquisition deficits. Behav. Neurosci. 110, 86–102 (1996).

    CAS  PubMed  Google Scholar 

  32. Saucier, D. & Cain, D. P. Spatial learning without NMDA receptor-dependent long-term potentiation. Nature 378, 186–189 (1995).

    CAS  PubMed  Google Scholar 

  33. Bannerman, D. M. et al. Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion. Nature Neurosci. 15, 1153–1159 (2012).

    CAS  PubMed  Google Scholar 

  34. Collingridge, G. L., Kehl, S. J. & McLennan, H. Excitatory amino acids in synaptic transmission in the Schaffer collateral–commissural pathway of the rat hippocampus. J. Physiol. 334, 33–46 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Morris, R. G., Anderson, E., Lynch, G. S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776 (1986).

    CAS  PubMed  Google Scholar 

  36. Morris, R. G. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J. Neurosci. 9, 3040–3057 (1989).

    CAS  PubMed  Google Scholar 

  37. Davis, S., Butcher, S. P. & Morris, R. G. The NMDA receptor antagonist D-2-amino-5- phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci. 12, 21–34 (1992).

    CAS  PubMed  Google Scholar 

  38. Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M. & Morris, R. G. Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182–186 (1995).

    CAS  PubMed  Google Scholar 

  39. Laube, B., Kuhse, J. & Betz, H. Evidence for a tetrameric structure of recombinant NMDA receptors. J. Neurosci. 18, 2954–2961 (1998).

    CAS  PubMed  Google Scholar 

  40. Seeburg, P. H. The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 16, 359–365 (1993).

    CAS  PubMed  Google Scholar 

  41. Sakimura, K. et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit. Nature 373, 151–155 (1995).

    CAS  PubMed  Google Scholar 

  42. Kiyama, Y. et al. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit. J. Neurosci. 18, 6704–6712 (1998).

    CAS  PubMed  Google Scholar 

  43. Bannerman, D. M. et al. NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory. J. Neurosci. 28, 3623–3630 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Tsien, J. Z. et al. Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87, 1317–1326 (1996).

    CAS  PubMed  Google Scholar 

  45. Tsien, J. Z., Huerta, P. T. & Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87, 1327–1338 (1996).

    CAS  PubMed  Google Scholar 

  46. Wiltgen, B. J. et al. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning. PLoS ONE 5, e12818 (2010).

    PubMed  PubMed Central  Google Scholar 

  47. Hoeffer, C. A. et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60, 832–845 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Fukaya, M., Kato, A., Lovett, C., Tonegawa, S. & Watanabe, M. Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc. Natl Acad. Sci. USA 100, 4855–4860 (2003).

    CAS  PubMed  Google Scholar 

  49. Brigman, J. L. et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J. Neurosci. 30, 4590–4600 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rondi-Reig, L. et al. Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation. J. Neurosci. 26, 4071–4081 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Niewoehner, B. et al. Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus. Eur. J. Neurosci. 25, 837–846 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Taylor, A. M. B. et al. Hippocampal NMDARs are important for behavioural inhibition but not for encoding associative spatial memories. Phil. Trans. R. Soc. B 369, 20130149 (2014).

    CAS  PubMed  Google Scholar 

  53. Phillips, R. G. & LeDoux, J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    CAS  PubMed  Google Scholar 

  54. Maren, S., Phan, K. L. & Liberzon, I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nature Rev. Neurosci. 14, 417–428 (2013).

    CAS  Google Scholar 

  55. Tsetsenis, T., Ma, X. H., Lo Iacono, L., Beck, S. G. & Gross, C. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nature Neurosci. 10, 896–902 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  57. Rolls, E. T. A theory of hippocampal function in memory. Hippocampus 6, 601–620 (1996).

    CAS  PubMed  Google Scholar 

  58. O'Reilly, R. C. & McClelland, J. L. Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus 4, 661–682 (1994).

    CAS  PubMed  Google Scholar 

  59. McNaughton, B. L. in Neural Connection, Mental Computation (eds Nadel, L., Cooper, L. A., & Culicover, P.) 285–350 (MIT Press, 1989).

    Google Scholar 

  60. Rolls, E. T. & Treves, A. Neural Networks and Brain Function (Oxford Univ. Press, 1998).

    Google Scholar 

  61. Shapiro, M. L. & Olton, D. S. in Memory Systems (eds Schacter, D. L. & Tulving, E.) 141–146 (MIT Press, 1994).

    Google Scholar 

  62. Gilbert, P. E., Kesner, R. P. & Lee, I. Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–636 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Clelland, C. D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Groves, J. O. L. et al. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic rat model. PLoS Genet. 9, e1003718 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Morris, R. G., Davis, S. & Butcher, S. P. Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Phil. Trans. R. Soc. Lond. B 329, 187–204 (1990).

    CAS  Google Scholar 

  67. von Engelhardt, J. et al. Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60, 846–860 (2008).

    CAS  PubMed  Google Scholar 

  68. Steele, R. J. & Morris, R. G. Delay-dependent impairment of a matching-to-place task with chronic and intrahippocampal infusion of the NMDA-antagonist D-AP5. Hippocampus 9, 118–136 (1999).

    CAS  PubMed  Google Scholar 

  69. Nakazawa, K. et al. Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38, 305–315 (2003).

    CAS  PubMed  Google Scholar 

  70. Nakazawa, K. et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science 297, 211–218 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Grover, L. M. & Teyler, T. J. N-methyl-D-aspartate receptor-independent long-term potentiation in area CA1 of rat hippocampus: input-specific induction and preclusion in a non-tetanized pathway. Neuroscience 49, 7–11 (1992).

    CAS  PubMed  Google Scholar 

  72. Silva, A. J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J. Neurobiol. 54, 224–237 (2003).

    CAS  PubMed  Google Scholar 

  73. Steffenach, H. A., Witter, M., Moser, M. B. & Moser, E. I. Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex. Neuron 45, 301–313 (2005).

    CAS  PubMed  Google Scholar 

  74. Mariano, T. Y. et al. Impulsive choice in hippocampal but not orbitofrontal cortex-lesioned rats on a nonspatial decision-making maze task. Eur. J. Neurosci. 30, 472–484 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Bannerman, D. M. et al. Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions. Behav. Neurosci. 113, 1170–1188 (1999).

    CAS  PubMed  Google Scholar 

  76. Fortin, N. J., Agster, K. L. & Eichenbaum, H. B. Critical role of the hippocampus in memory for sequences of events. Nature Neurosci. 5, 458–462 (2002).

    CAS  PubMed  Google Scholar 

  77. Kesner, R. P., Gilbert, P. E. & Barua, L. A. The role of the hippocampus in memory for the temporal order of a sequence of odors. Behav. Neurosci. 116, 286–290 (2002).

    PubMed  Google Scholar 

  78. Marshall, V. J., McGregor, A., Good, M. & Honey, R. C. Hippocampal lesions modulate both associative and nonassociative priming. Behav. Neurosci. 118, 377–382 (2004).

    CAS  PubMed  Google Scholar 

  79. Honey, R. C. & Good, M. Associative modulation of the orienting response: distinct effects revealed by hippocampal lesions. J. Exp. Psychol. Anim. Behav. Process 26, 3–14 (2000).

    CAS  PubMed  Google Scholar 

  80. Gray, J. A. The Neuropsychology of Anxiety 1st edn (Oxford Univ. Press, 1982).

    Google Scholar 

  81. Gray, J. A. & McNaughton, N. The Neuropsychology of Anxiety 2nd edn (Oxford Univ. Press, 2000).

    Google Scholar 

  82. Hasler, G. et al. Cerebral blood flow in immediate and sustained anxiety. J. Neurosci. 27, 6313–6319 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    CAS  PubMed  Google Scholar 

  84. Holick, K. A., Lee, D. C., Hen, R. & Dulawa, S. C. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33, 406–417 (2008).

    CAS  PubMed  Google Scholar 

  85. Deacon, R. M., Bannerman, D. M. & Rawlins, J. N. Anxiolytic effects of cytotoxic hippocampal lesions in rats. Behav. Neurosci. 116, 494–497 (2002).

    PubMed  Google Scholar 

  86. Treit, D. & Menard, J. Dissociations among the anxiolytic effects of septal, hippocampal, and amygdaloid lesions. Behav. Neurosci. 111, 653–658 (1997).

    CAS  PubMed  Google Scholar 

  87. Barkus, C. et al. Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion. Eur. J. Pharmacol. 626, 49–56 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Witter, M. P. A survey of the anatomy of the hippocampal formation, with emphasis on the septotemporal organization of its intrinsic and extrinsic connections. Adv. Exp. Med. Biol. 203, 67–82 (1986).

    CAS  PubMed  Google Scholar 

  89. Siegel, A. & Tassoni, J. P. Differential efferent projections from the ventral and dorsal hippocampus of the cat. Brain, Behav. Evol. 4, 185–200 (1971).

    CAS  Google Scholar 

  90. Moser, M. B. & Moser, E. I. Functional differentiation in the hippocampus. Hippocampus 8, 608–619 (1998).

    CAS  PubMed  Google Scholar 

  91. Swanson, L. W. & Cowan, W. M. An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat. J. Comp. Neurol. 172, 49–84 (1977).

    CAS  PubMed  Google Scholar 

  92. Moser, E., Moser, M. B. & Andersen, P. Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J. Neurosci. 13, 3916–3925 (1993).

    CAS  PubMed  Google Scholar 

  93. Moser, M. B., Moser, E. I., Forrest, E., Andersen, P. & Morris, R. G. Spatial learning with a minislab in the dorsal hippocampus. Proc. Natl Acad. Sci. USA 92, 9697–9701 (1995).

    CAS  PubMed  Google Scholar 

  94. Hock, B. J. Jr & Bunsey, M. D. Differential effects of dorsal and ventral hippocampal lesions. J. Neurosci. 18, 7027–7032 (1998).

    CAS  PubMed  Google Scholar 

  95. Bannerman, D. M. et al. Double dissociation of function within the hippocampus: spatial memory and hyponeophagia. Behav. Neurosci. 116, 884–901 (2002).

    CAS  PubMed  Google Scholar 

  96. Pothuizen, H. H., Zhang, W. N., Jongen-Relo, A. L., Feldon, J. & Yee, B. K. Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory. Eur. J. Neurosci. 19, 705–712 (2004).

    PubMed  Google Scholar 

  97. Bannerman, D. M. et al. Ventral hippocampal lesions affect anxiety but not spatial learning. Behav. Brain Res. 139, 197–213 (2003).

    CAS  PubMed  Google Scholar 

  98. Kjelstrup, K. G. et al. Reduced fear expression after lesions of the ventral hippocampus. Proc. Natl Acad. Sci. USA 99, 10825–10830 (2002).

    CAS  PubMed  Google Scholar 

  99. McHugh, S. B., Deacon, R. M., Rawlins, J. N. & Bannerman, D. M. Amygdala and ventral hippocampus contribute differentially to mechanisms of fear and anxiety. Behav. Neurosci. 118, 63–78 (2004).

    CAS  PubMed  Google Scholar 

  100. Chudasama, Y., Wright, K. S. & Murray, E. A. Hippocampal lesions in rhesus monkeys disrupt emotional responses but not reinforcer devaluation effects. Biol. Psychiatry 63, 1084–1091 (2008).

    PubMed  Google Scholar 

  101. Pentkowski, N. S., Blanchard, D. C., Lever, C., Litvin, Y. & Blanchard, R. J. Effects of lesions to the dorsal and ventral hippocampus on defensive behaviors in rats. Eur. J. Neurosci. 23, 2185–2196 (2006).

    PubMed  Google Scholar 

  102. Maren, S. Neurotoxic or electrolytic lesions of the ventral subiculum produce deficits in the acquisition and expression of Pavlovian fear conditioning in rats. Behav. Neurosci. 113, 283–290 (1999).

    CAS  PubMed  Google Scholar 

  103. Richmond, M. A. et al. Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning. Behav. Neurosci. 113, 1189–1203 (1999).

    CAS  PubMed  Google Scholar 

  104. McHugh, S. B., Campbell, T. G., Taylor, A. M., Rawlins, J. N. & Bannerman, D. M. A role for dorsal and ventral hippocampus in inter-temporal choice cost–benefit decision making. Behav. Neurosci. 122, 1–8 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hartley, T., Maguire, E. A., Spiers, H. J. & Burgess, N. The well-worn route and the path less traveled: distinct neural bases of route following and wayfinding in humans. Neuron 37, 877–888 (2003).

    CAS  PubMed  Google Scholar 

  106. Kumaran, D. & Maguire, E. A. The human hippocampus: cognitive maps or relational memory? J. Neurosci. 25, 7254–7259 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Maguire, E. A., Frackowiak, R. S. & Frith, C. D. Recalling routes around london: activation of the right hippocampus in taxi drivers. J. Neurosci. 17, 7103–7110 (1997).

    CAS  PubMed  Google Scholar 

  108. Maguire, E. A. et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Natl Acad. Sci. USA 97, 4398–4403 (2000).

    CAS  PubMed  Google Scholar 

  109. Alvarez, R. P., Biggs, A., Chen, G., Pine, D. S. & Grillon, C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J. Neurosci. 28, 6211–6219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Bast, T., Wilson, I. A., Witter, M. P. & Morris, R. G. From rapid place learning to behavioral performance: a key role for the intermediate hippocampus. PLoS Biol. 7, e1000089 (2009).

    PubMed  PubMed Central  Google Scholar 

  112. Vinogradova, O. S. in The Hippocampus Vol. 2 (eds Isaacson, R. I. & Pribram, K. H.) 3–69 (Plenum, 1975).

    Google Scholar 

  113. Jarrard, L. & Isaacson, R. L. Runway response perseveration in the hippocampectomised rat: determined by extinction variables. Nature 207, 109–110 (1965).

    Google Scholar 

  114. Clark, C. V. & Isaacson, R. L. Effect of bilateral hippocampal ablation on Drl performance. J. Comp. Physiol. Psychol. 59, 137–140 (1965).

    CAS  PubMed  Google Scholar 

  115. Douglas, R. J. The hippocampus and behavior. Psychol. Bull. 67, 416–422 (1967).

    CAS  PubMed  Google Scholar 

  116. Davidson, T. L. & Jarrard, L. E. The hippocampus and inhibitory learning: a 'Gray' area? Neurosci. Biobehav Rev. 28, 261–271 (2004).

    CAS  PubMed  Google Scholar 

  117. Kimble, D. P. & Kimble, R. J. Hippocampectomy and response perseveration in the rat. J. Comp. Physiol. Psychol. 60, 474–476 (1965).

    CAS  PubMed  Google Scholar 

  118. Lisman, J. E. & Grace, A. A. The hippocampal–VTA loop: controlling the entry of information into long-term memory. Neuron 46, 703–713 (2005).

    CAS  PubMed  Google Scholar 

  119. Hollerman, J. R. & Schultz, W. Dopamine neurons report an error in the temporal prediction of reward during learning. Nature Neurosci. 1, 304–309 (1998).

    CAS  PubMed  Google Scholar 

  120. Ploghaus, A. et al. Learning about pain: the neural substrate of the prediction error for aversive events. Proc. Natl Acad. Sci. USA 97, 9281–9286 (2000).

    CAS  PubMed  Google Scholar 

  121. Han, J. S., Gallagher, M. & Holland, P. Hippocampal lesions disrupt decrements but not increments in conditioned stimulus processing. J. Neurosci. 15, 7323–7329 (1995).

    CAS  PubMed  Google Scholar 

  122. Kumaran, D. & Maguire, E. A. Match mismatch processes underlie human hippocampal responses to associative novelty. J. Neurosci. 27, 8517–8524 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kumaran, D. & Maguire, E. A. An unexpected sequence of events: mismatch detection in the human hippocampus. PLoS Biol. 4, e424 (2006).

    PubMed  PubMed Central  Google Scholar 

  124. O'Keefe, J. Place units in the hippocampus of the freely moving rat. Exp. Neurol. 51, 78–109 (1976).

    CAS  PubMed  Google Scholar 

  125. Fyhn, M., Molden, S., Hollup, S., Moser, M. B. & Moser, E. Hippocampal neurons responding to first-time dislocation of a target object. Neuron 35, 555–566 (2002).

    CAS  PubMed  Google Scholar 

  126. Honey, R. C. & Good, M. Associative components of recognition memory. Curr. Opin. Neurobiol. 10, 200–204 (2000).

    CAS  PubMed  Google Scholar 

  127. Honey, R. C., Watt, A. & Good, M. Hippocampal lesions disrupt an associative mismatch process. J. Neurosci. 18, 2226–2230 (1998).

    CAS  PubMed  Google Scholar 

  128. Resnik, E., McFarland, J. M., Sprengel, R., Sakmann, B. & Mehta, M. R. The effects of GluA1 deletion on the hippocampal population code for position. J. Neurosci. 32, 8952–8968 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Reisel, D. et al. Spatial memory dissociations in mice lacking GluR1. Nature Neurosci. 5, 868–873 (2002).

    CAS  PubMed  Google Scholar 

  130. Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999).

    CAS  PubMed  Google Scholar 

  131. Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J. & Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68, 557–569 (2010).

    CAS  PubMed  Google Scholar 

  132. Allen, K., Fuchs, E. C., Jaschonek, H., Bannerman, D. M. & Monyer, H. Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. J. Neurosci. 31, 6542–6552 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Caputi, A., Fuchs, E. C., Allen, K., Le Magueresse, C. & Monyer, H. Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity. PLoS ONE 7, e37318 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Lisman, J. E. Role of the dual entorhinal inputs to hippocampus: a hypothesis based on cue/action (non-self/self) couplets. Prog. Brain Res. 163, 615–625 (2007).

    PubMed  Google Scholar 

  135. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    CAS  PubMed  Google Scholar 

  136. Kessels, H. W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Erickson, M. A., Maramara, L. A. & Lisman, J. A single brief burst induces GluR1-dependent associative short-term potentiation: a potential mechanism for short-term memory. J. Cogn. Neurosci. 22, 2530–2540 (2010).

    PubMed  PubMed Central  Google Scholar 

  138. Hoffman, D. A., Sprengel, R. & Sakmann, B. Molecular dissection of hippocampal theta-burst pairing potentiation. Proc. Natl Acad. Sci. USA 99, 7740–7745 (2002).

    CAS  PubMed  Google Scholar 

  139. Romberg, C. et al. Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus. Eur. J. Neurosci. 29, 1141–1152 (2009).

    PubMed  PubMed Central  Google Scholar 

  140. Schmitt, W. B. et al. Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice. Nature Neurosci. 8, 270–272 (2005).

    CAS  PubMed  Google Scholar 

  141. Sanderson, D. J. et al. Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory. Behav. Neurosci. 121, 559–569 (2007).

    CAS  PubMed  Google Scholar 

  142. Sanderson, D. J. et al. Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory. Learn. Mem. 18, 181–190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Sanderson, D. J., Sprengel, R., Seeburg, P. H. & Bannerman, D. M. Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory. Learn. Mem. 18, 128–131 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Wagner, A. R. in Information Processing in Animals: Memory Mechanisms (eds Spear, N. E. & Miller, R. R.) 5–47 (Erlbaum, 1981).

    Google Scholar 

  145. Brandon, S. E., Vogel, E. H. & Wagner, A. R. Stimulus representation in SOP: I. theoretical rationalization and some implications. Behav. Processes 62, 5–25 (2003).

    PubMed  Google Scholar 

  146. Fuchs, E. C. et al. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron 53, 591–604 (2007).

    CAS  PubMed  Google Scholar 

  147. Murray, A. J. et al. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nature Neurosci. 14, 297–299 (2011).

    CAS  PubMed  Google Scholar 

  148. Gray, C. M. & Singer, W. Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc. Natl Acad. Sci. USA 86, 1698–1702 (1989).

    CAS  PubMed  Google Scholar 

  149. Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Wellcome trust (grants 074385 and 087736 to D.M.B.), the European Research Council (GABAcellsAndMemory grant 250047 to H.M.), the Deutsche Forschungsgemeinschaft (SFB 636/A4 to R.S.) and the Max Planck Society (to R.S. and P.H.S.).

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Correspondence to David M. Bannerman or Peter H. Seeburg.

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Glossary

AP5

(2-amino-5-phosphopentanoate). A competitive antagonist of the NMDA-type glutamate receptor. The drug competes with glutamate to bind to the NMDA receptor and thus reduces the activity of these receptors.

Boundary vector cells

The firing of these cells depends solely on the animal's location relative to environmental boundaries and is independent of the animal's heading direction.

Dissociations

A term to describe when an experimental manipulation (for example, a lesion, genetic modification or drug treatment) affects performance on one behavioural task but not another. This is taken to suggest that different neural substrates may underlie the two behaviours.

Double dissociation

A term to describe when a given experimental manipulation affects task A but not task B, whereas a second manipulation affects task B but does not affect task A. A double dissociation is evidence that these behaviours must be supported by different neural substrates.

Grid cells

Cells that have been found in layer 2/3 of the medial entorhinal cortex and that fire at several regularly spaced locations (unlike hippocampal place cells, which fire only in one part of a given environment), with marked inhibition of firing outside these locations.

Head direction cells

Cells that are sensitive to the orientation of the animal's head with respect to the environmental frame, irrespective of the animal's spatial location within that environment. They signal a single preferred head direction, irrespective of body-orientation or current position; whether the animal is moving or stationary.

Place cells

Cells that selectively increase their firing rate only when the animal occupies a well-defined, small patch of the environment (the place field), and they rarely fire outside this region. Place cells are usually recorded in the hippocampus proper, but they are also present in other areas of the hippocampal formation (for example, the entorhinal cortex, subiculum, presubiculum and parasubiculum).

Spatial reference memory

(SRM).The ability to learn a consistent, fixed response to a spatial stimulus, reflecting a constant association between that spatial location and an outcome. For example, an animal will need to learn the spatial location of its home burrow or a reliable water source that is constant within the environment.

Spatial working memory

(SWM). The ability to maintain trial-specific information for a limited period of time so that spatial responses can be made in a flexible manner from trial to trial. This is the basis of foraging behaviour (for example, remembering where you have just been so that you can adopt an efficient search strategy).

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Bannerman, D., Sprengel, R., Sanderson, D. et al. Hippocampal synaptic plasticity, spatial memory and anxiety. Nat Rev Neurosci 15, 181–192 (2014). https://doi.org/10.1038/nrn3677

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