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  • Review Article
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Functional organization of the hippocampal longitudinal axis

Nature Reviews Neuroscience volume 15, pages 655–669 (2014)Cite this article

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Key Points

  • The currently accepted model of a dorsal–ventral (posterior–anterior) dichotomy of hippocampal function requires revision.

  • There is evidence for two types of long-axis organization: gradients and discrete transitions.

  • Anatomical studies in rodents and primates show that hippocampal extrinsic connectivity is organized as smooth topographical gradients. The relative size of spatial representation by place cells in the rat hippocampus gradually increases from dorsal to ventral.

  • By contrast, rodent gene expression studies demonstrate multiple long-axis functional domains with sharply demarcated borders: at least nine in CA3 and three in CA1 and the dentate gyrus.

  • Hippocampal intrinsic anatomical connectivity, as well as electrophysiological measures of coherence, show abrupt division from the ventral (anterior) one-third to dorsal (posterior) two-thirds of the hippocampus.

  • Hippocampal involvement in unconditioned fear responses is limited to the ventral one-third.

  • When these levels of organization are superimposed, a new model of hippocampal long-axis organization emerges: gradients with discrete domains, the latter dividing the hippocampus into (at least) three portions along the long axis.

  • This model supersedes a simple dissociation of the dorsal from the ventral hippocampus and provides a potential framework for accommodating the multiple functions ascribed to the hippocampus in rodents and primates.

Abstract

The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus.

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Figure 1: Cross-species comparison of hippocampal anatomy.
Figure 2: Extrinsic connectivity gradients.
Figure 3: Discrete transitions in the molecular, anatomical and functional organization of the hippocampal long axis.
Figure 4: Schematic of superimposed patterns of long-axis organization.
Figure 5: Gradients for space in the medial temporal lobe in rodents and monkeys.
Figure 6: Forming non-sequential, higher-order connections in the human hippocampus.

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References

  1. Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Clarendon, 1978).

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

    PubMed  Google Scholar 

  6. Strange, B. A., Fletcher, P. C., Henson, R. N. A., Friston, K. J. & Dolan, R. J. Segregating the functions of human hippocampus. Proc. Natl Acad. Sci. USA 96, 4034–4039 (1999). The first experimental demonstration, using fMRI, of a double dissociation in anterior versus posterior human hippocampal responses.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Corkin, S. Acquisition of motor skill after bilateral medial temporal-lobe excision. Neuropsychologia 6, 255–265 (1968).

    Google Scholar 

  9. 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 

  10. O'Keefe, J. & Speakman, A. Single unit activity in the rat hippocampus during a spatial memory task. Exp. Brain Res. 68, 1–27 (1987).

    CAS  PubMed  Google Scholar 

  11. Cave, C. B. & Squire, L. R. Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus. Hippocampus 1, 329–340 (1991).

    CAS  PubMed  Google Scholar 

  12. Nadel, L. The hippocampus and space revisited. Hippocampus 1, 221–229 (1991).

    CAS  PubMed  Google Scholar 

  13. Kim, J. J. & Fanselow, M. S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Elul, R. Regional differences in the hippocampus of the cat. I. Specific discharge patterns of the dorsal and ventral hippocampus and their role in generalized seizures. Electroencephalogr. Clin. Neurophysiol. 16, 470–488 (1964).

    CAS  PubMed  Google Scholar 

  16. Racine, R., Rose, P. A. & Burnham, W. M. Afterdischarge thresholds and kindling rates in dorsal and ventral hippocampus and dentate gyrus. Can. J. Neurol. Sci. 4, 273–278 (1977).

    CAS  PubMed  Google Scholar 

  17. Hughes, K. R. Dorsal and ventral hippocampus lesions and maze learning: influence of preoperative environment. Can. J. Psychol. 19, 325–332 (1965).

    CAS  PubMed  Google Scholar 

  18. Nadel, L. Dorsal and ventral hippocampal lesions and behavior. Physiol. Behav. 3, 891–900 (1968).

    Google Scholar 

  19. Stevens, R. & Cowey, A. Effects of dorsal and ventral hippocampal lesions on spontaneous alternation, learned alternation and probability learning in rats. Brain Res. 52, 203–224 (1973).

    CAS  PubMed  Google Scholar 

  20. Sinnamon, H., Freniere, S. & Kootz, J. Rat hippocampus and memory for places of changing significance. J. Comp. Physiol. Psychol. 92, 142–155 (1978).

    CAS  PubMed  Google Scholar 

  21. 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). This study, along with that reported in reference 22, made an important advance in localizing rodent spatial function predominantly to the dorsal hippocampus. By controlling the size and locus of hippocampal lesions, this work demonstrated that restricted dorsal hippocampal lesions, but not similarly sized ventral lesions, impaired spatial learning.

    CAS  PubMed  Google Scholar 

  22. 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 

  23. Gray, J. A. & McNaughton, N. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System (Oxford Univ. Press,1982).

    Google Scholar 

  24. van Groen, T. & Wyss, J. M. Extrinsic projections from area CA1 of the rat hippocampus: olfactory, cortical, subcortical, and bilateral hippocampal formation projections. J. Comp. Neurol. 302, 515–528 (1990).

    CAS  PubMed  Google Scholar 

  25. Canteras, N. & Swanson, L. W. Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: a PHA-L anterograde tracing study in the rat. J. Comp. Neurol. 324, 180–194 (1992).

    CAS  PubMed  Google Scholar 

  26. Risold, P. Y. & Swanson, L. W. Structural evidence for functional domains in the rat hippocampus. Science 272, 1484–1486 (1996). A beautiful demonstration of topographical hippocampal connectivity with subcortical areas, this is one of the earliest studies to imply that the hippocampal long axis could comprise multiple domains as opposed to a ventral–dorsal dichotomy.

    CAS  PubMed  Google Scholar 

  27. Henke, P. G. Hippocampal pathway to the amygdala and stress ulcer development. Brain Res. Bull. 25, 691–695 (1990).

    CAS  PubMed  Google Scholar 

  28. Bannerman, D. M. et al. Regional dissociations within the hippocampus—memory and anxiety. Neurosci. Biobehav. Rev. 28, 273–283 (2004).

    CAS  PubMed  Google Scholar 

  29. 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 

  30. Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989). A landmark synthesis of anatomical data, in which the organization of inputs along the hippocampal long axis was emphasized, as well as the longitudinal distribution of intrinsic hippocampal pathways.

    CAS  PubMed  Google Scholar 

  31. Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008). The first evidence for a gradient of function in the rodent hippocampal long axis. A gradual increase in place field size from the dorsal to ventral hippocampus also indicates that the ventral hippocampus may subserve similar spatial processing functions as the dorsal hippocampus, but at a larger spatial scale.

    CAS  PubMed  Google Scholar 

  32. Thompson, C. L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008). A major advance in our understanding of functional divisions of the hippocampal long axis. The techniques developed in reference 42 were applied to show that CA3 can be divided into nine discrete domains on the basis of gene expression.

    CAS  PubMed  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. Witter, M. P., Wouterlood, F. G., Naber, P. A. & Van Haeften, T. Anatomical organization of the parahippocampal-hippocampal network. Ann. NY Acad. Sci. 911, 1–24 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  36. Jones, B. F. & Witter, M. P. Cingulate cortex projections to the parahippocampal region and hippocampal formation in the rat. Hippocampus 17, 957–976 (2007).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  38. Risold, P. & Swanson, L. Connections of the rat lateral septal complex. Brain Res. Rev. 24, 115–195 (1997).

    CAS  PubMed  Google Scholar 

  39. Groenewegen, H. J., Vermeulen-Van der Zee, E., te Kortschot, A. & Witter, M. P. Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23, 103–120 (1987).

    CAS  PubMed  Google Scholar 

  40. Kishi, T., Tsumori, T., Yokota, S. & Yasui, Y. Topographical projection from the hippocampal formation to the amygdala: a combined anterograde and retrograde tracing study in the rat. J. Comp. Neurol. 496, 349–368 (2006).

    PubMed  Google Scholar 

  41. Bayer, S. A. & Altman, J. Directions in neurogenetic gradients and patterns of anatomical connections in the telencephalon. Prog. Neurobiol. 29, 57–106 (1987).

    CAS  PubMed  Google Scholar 

  42. Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007).

    CAS  PubMed  Google Scholar 

  43. Dong, H. W., Swanson, L. W., Chen, L., Fanselow, M. S. & Toga, A. W. Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc. Natl Acad. Sci. USA 106, 11794–11799 (2009).

    CAS  PubMed  Google Scholar 

  44. O'Reilly, K. C. et al. Identification of dorsal–ventral hippocampal differentiation in neonatal rats. Brain Struct. Funct. http://dx.doi.org/10.1007/s00429-014-0831-8 (2014).

  45. Dougherty, K. A., Islam, T. & Johnston, D. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus. J. Physiol. 590, 5707–5722 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Maggio, N. & Segal, M. Striking variations in corticosteroid modulation of long-term potentiation along the septotemporal axis of the hippocampus. J. Neurosci. 27, 5757–5765 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Papatheodoropoulos, C. & Kostopoulos, G. Decreased ability of rat temporal hippocampal CA1 region to produce long-term potentiation. Neurosci. Lett. 279, 177–180 (2000).

    CAS  PubMed  Google Scholar 

  48. Dougherty, K. et al. Differential expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. J. Neurophysiol. 109, 1940–1953 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hussaini, S. A., Kempadoo, K. A., Thuault, S. J., Siegelbaum, S. A. & Kandel, E. R. Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. Neuron 72, 643–653 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Giocomo, L. M. et al. Grid cells use HCN1 channels for spatial scaling. Cell 147, 1159–1170 (2011).

    CAS  PubMed  Google Scholar 

  51. Garden, D. L., Dodson, P. D., O'Donnell, C., White, M. D. & Nolan, M. F. Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields. Neuron 60, 875–889 (2008).

    CAS  PubMed  Google Scholar 

  52. Deguchi, Y., Donato, F., Galimberti, I., Cabuy, E. & Caroni, P. Temporally matched subpopulations of selectively interconnected principal neurons in the hippocampus. Nature Neurosci. 14, 495–504 (2011).

    CAS  PubMed  Google Scholar 

  53. Moser, E. I. The multi-laned hippocampus. Nature Neurosci. 14, 407–408 (2011).

    CAS  PubMed  Google Scholar 

  54. Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, X. G., Somogyi, P., Ylinen, A. & Buzsaki, G. The hippocampal CA3 network: an in vivo intracellular labeling study. J. Comp. Neurol. 339, 181–208 (1994).

    CAS  PubMed  Google Scholar 

  56. Ishizuka, N., Weber, J. & Amaral, D. G. Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J. Comp. Neurol. 295, 580–623 (1990).

    CAS  PubMed  Google Scholar 

  57. Swanson, L. W., Wyss, J. M. & Cowan, W. M. An autoradiographic study of the organization of intrahippocampal association pathways in the rat. J. Comp. Neurol. 181, 681–715 (1978).

    CAS  PubMed  Google Scholar 

  58. Fricke, R. & Cowan, W. M. An autoradiographic study of the commissural and ipsilateral hippocampo-dentate projections in the adult rat. J. Comp. Neurol. 181, 253–269 (1978).

    CAS  PubMed  Google Scholar 

  59. Kondo, H., Lavenex, P. & Amaral, D. G. Intrinsic connections of the macaque monkey hippocampal formation: II. CA3 connections. J. Comp. Neurol. 515, 349–377 (2009).

    PubMed  PubMed Central  Google Scholar 

  60. Staresina, B. P., Fell, J., Do Lam, A. T., Axmacher, N. & Henson, R. N. Memory signals are temporally dissociated in and across human hippocampus and perirhinal cortex. Nature Neurosci. 15, 1167–1173 (2012).

    CAS  PubMed  Google Scholar 

  61. Patel, J., Fujisawa, S., Berényi, A., Royer, S. & Buzsáki, G. Traveling theta waves along the entire septotemporal axis of the hippocampus. Neuron 75, 410–417 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  63. Moser, M. B. & Moser, E. I. Distributed encoding and retrieval of spatial memory in the hippocampus. J. Neurosci. 18, 7535–7542 (1998).

    CAS  PubMed  Google Scholar 

  64. Jung, M. W., Wiener, S. I. & McNaughton, B. L. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J. Neurosci. 14, 7347–7356 (1994).

    CAS  PubMed  Google Scholar 

  65. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kraus, B. J. et al. Hippocampal “time cells”: time versus path integration. Neuron 78, 1090–1101 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Pilly, P. K. & Grossberg, S. How do spatial learning and memory occur in the brain? Coordinated learning of entorhinal grid cells and hippocampal place cells. J. Cogn. Neurosci. 24, 1031–1054 (2012).

    PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  Google Scholar 

  70. Colgin, L. L., Moser, E. I. & Moser, M. B. Understanding memory through hippocampal remapping. Trends Neurosci. 31, 469–477 (2008).

    CAS  PubMed  Google Scholar 

  71. 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 

  72. O'Keefe, J. & Burgess, N. Dual phase and rate coding in hippocampal place cells: theoretical significance and relationship to entorhinal grid cells. Hippocampus 15, 853–866 (2005).

    PubMed  PubMed Central  Google Scholar 

  73. McNaughton, B. L., Battaglia, F. P., Jensen, O., Moser, E. I. & Moser, M. B. Path integration and the neural basis of the 'cognitive map'. Nature Rev. Neurosci. 7, 663–678 (2006).

    CAS  Google Scholar 

  74. Fuhs, M. C. & Touretzky, D. S. A spin glass model of path integration in rat medial entorhinal cortex. J. Neurosci. 26, 4266–4276 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Solstad, T., Moser, E. I. & Einevoll, G. T. From grid cells to place cells: a mathematical model. Hippocampus 16, 1026–1031 (2006).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  77. Maurer, A. P., Vanrhoads, S. R., Sutherland, G. R., Lipa, P. & McNaughton, B. L. Self-motion and the origin of differential spatial scaling along the septo-temporal axis of the hippocampus. Hippocampus 15, 841–852 (2005).

    PubMed  Google Scholar 

  78. 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 

  79. Brun, V. H. et al. Progressive increase in grid scale from dorsal to ventral medial entorhinal cortex. Hippocampus 18, 1200–1212 (2008).

    PubMed  Google Scholar 

  80. Stensola, H. et al. The entorhinal grid map is discretized. Nature 492, 72–78 (2012). The discovery of discrete modules of grid-cell clusters in the rat EC that maintain grid scale and respond independently to the environment is important for understanding the increase in place field size along the hippocampal dorsoventral axis, as it raises the possibility that the latter is also discretized.

    CAS  PubMed  Google Scholar 

  81. 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).

    CAS  PubMed  Google Scholar 

  82. O'Keefe, J. & Burgess, N. Geometric determinants of the place fields of hippocampal neurons. Nature 381, 425–428 (1996).

    CAS  PubMed  Google Scholar 

  83. Greicius, M. D. et al. Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study. Hippocampus 13, 164–174 (2003).

    PubMed  Google Scholar 

  84. Preston, A. R., Thomason, M. E., Ochsner, K. N., Cooper, J. C. & Glover, G. H. Comparison of spiral-in/out and spiral-out BOLD fMRI at 1.5 and 3 T. Neuroimage 21, 291–301 (2004).

    PubMed  Google Scholar 

  85. 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 

  86. Suthana, N. A., Ekstrom, A. D., Moshirvaziri, S., Knowlton, B. & Bookheimer, S. Y. Human hippocampal CA1 involvement during allocentric encoding of spatial information. J. Neurosci. 29, 10512–10519 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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 

  88. Nadel, L., Hoscheidt, S. & Ryan, L. R. Spatial cognition and the hippocampus: the anterior–posterior axis. J. Cogn. Neurosci. 25, 22–28 (2013).

    PubMed  Google Scholar 

  89. Wolbers, T. & Buchel, C. Dissociable retrosplenial and hippocampal contributions to successful formation of survey representations. J. Neurosci. 25, 3333–3340 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Doeller, C. F., King, J. A. & Burgess, N. Parallel striatal and hippocampal systems for landmarks and boundaries in spatial memory. Proc. Natl Acad. Sci. USA 105, 5915–5920 (2008).

    CAS  PubMed  Google Scholar 

  91. Baumann, O. & Mattingley, J. B. Dissociable representations of environmental size and complexity in the human hippocampus. J. Neurosci. 33, 10526–10533 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Miller, J. F. et al. Neural activity in human hippocampal formation reveals the spatial context of retrieved memories. Science 342, 1111–1114 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Colombo, M., Fernandez, T., Nakamura, K. & Gross, C. G. Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys. J. Neurophysiol. 80, 1002–1005 (1998).

    CAS  PubMed  Google Scholar 

  94. Ekstrom, A. D. et al. Cellular networks underlying human spatial navigation. Nature 425, 184–188 (2003).

    CAS  PubMed  Google Scholar 

  95. Killian, N. J., Jutras, M. J. & Buffalo, E. A. A map of visual space in the primate entorhinal cortex. Nature 491, 761–764 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zeineh, M. M., Engel, S. A., Thompson, P. M. & Bookheimer, S. Y. Dynamics of the hippocampus during encoding and retrieval of face-name pairs. Science 299, 577–580 (2003). This important methodological advance in human MRI of the hippocampus was the forerunner for now a large number of high-resolution hippocampal fMRI studies that localize activity to different hippocampal subregions.

    CAS  PubMed  Google Scholar 

  97. Ekstrom, A. D. et al. Advances in high-resolution imaging and computational unfolding of the human hippocampus. Neuroimage 47, 42–49 (2009).

    PubMed  PubMed Central  Google Scholar 

  98. Carr, V. A., Rissman, J. & Wagner, A. D. Imaging the human medial temporal lobe with high-resolution fMRI. Neuron 65, 298–308 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Derdikman, D. et al. Fragmentation of grid cell maps in a multicompartment environment. Nature Neurosci. 12, 1325–1332 (2009).

    CAS  PubMed  Google Scholar 

  100. Terrazas, A. et al. Self-motion and the hippocampal spatial metric. J. Neurosci. 25, 8085–8096 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pikkarainen, M., Rönkkö, S., Savander, V., Insausti, R. & Pitkänen, A. Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat. J. Comp. Neurol. 403, 229–260 (1999).

    CAS  PubMed  Google Scholar 

  102. Petrovich, G. D., Canteras, N. S. & Swanson, L. W. Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems. Brain Res. Rev. 38, 247–289 (2001).

    CAS  PubMed  Google Scholar 

  103. Pitkänen, A., Pikkarainen, M., Nurminen, N. & Ylinen, A. Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat: a review. Ann. NY Acad. Sci. 911, 369–391 (2000).

    PubMed  Google Scholar 

  104. Fanselow, M. S. & LeDoux, J. E. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23, 229–232 (1999).

    CAS  PubMed  Google Scholar 

  105. Bast, T., Zhang, W. N. & Feldon, J. The ventral hippocampus and fear conditioning in rats. Different anterograde amnesias of fear after tetrodotoxin inactivation and infusion of the GABAA agonist muscimol. Exp. Brain Res. 139, 39–52 (2001).

    CAS  PubMed  Google Scholar 

  106. Maren, S., Aharonov, G. & Fanselow, M. S. Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav. Brain Res. 88, 261–274 (1997).

    CAS  PubMed  Google Scholar 

  107. Carvalho, M. C., Masson, S., Brandao, M. L. & de Souza Silva, M. A. Anxiolytic-like effects of substance P administration into the dorsal, but not ventral, hippocampus and its influence on serotonin. Peptides 29, 1191–1200 (2008).

    CAS  PubMed  Google Scholar 

  108. Fudge, J. L., Decampo, D. & Becoats, K. Revisiting the hippocampal–amygdala pathway in primates: association with immature-appearing neurons. Neuroscience 212, 104–119 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Dolcos, F., LaBar, K. S. & Cabeza, R. Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42, 855–863 (2004).

    CAS  PubMed  Google Scholar 

  110. Murty, V. P., Ritchey, M., Adcock, R. A. & LaBar, K. S. fMRI studies of successful emotional memory encoding: a quantitative meta-analysis. Neuropsychologia 48, 3459–3469 (2010).

    PubMed  PubMed Central  Google Scholar 

  111. Kensinger, E. A. & Schacter, D. L. Amygdala activity is associated with the successful encoding of item, but not source, information for positive and negative stimuli. J. Neurosci. 26, 2564–2570 (2006).

    CAS  PubMed  Google Scholar 

  112. 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 

  113. 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 

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

    CAS  PubMed  Google Scholar 

  115. Moita, M. A., Rosis, S., Zhou, Y., LeDoux, J. E. & Blair, H. T. Hippocampal place cells acquire location-specific responses to the conditioned stimulus during auditory fear conditioning. Neuron 37, 485–497 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  117. Halgren, E. Firing of human hippocampal units in relation to voluntary movements. Hippocampus 1, 153–161 (1991).

    CAS  PubMed  Google Scholar 

  118. Thoenissen, D., Zilles, K. & Toni, I. Differential involvement of parietal and precentral regions in movement preparation and motor intention. J. Neurosci. 22, 9024–9034 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang, W. N., Bast, T. & Feldon, J. Effects of hippocampal N-methyl-D-aspartate infusion on locomotor activity and prepulse inhibition: differences between the dorsal and ventral hippocampus. Behav. Neurosci. 116, 72–84 (2002).

    CAS  PubMed  Google Scholar 

  120. Peleg-Raibstein, D. & Feldon, J. Effects of dorsal and ventral hippocampal NMDA stimulation on nucleus accumbens core and shell dopamine release. Neuropharmacology 51, 947–957 (2006).

    CAS  PubMed  Google Scholar 

  121. Bardgett, M. E. & Henry, J. D. Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors. Neuroscience 94, 59–70 (1999).

    CAS  PubMed  Google Scholar 

  122. Wu, M. & Brudzynski, S. M. Mesolimbic dopamine terminals and locomotor activity induced from the subiculum. Neuroreport 6, 1601–1604 (1995).

    CAS  PubMed  Google Scholar 

  123. Legault, M., Rompre, P. P. & Wise, R. A. Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. J. Neurosci. 20, 1635–1642 (2000).

    CAS  PubMed  Google Scholar 

  124. Royer, S., Sirota, A., Patel, J. & Buzsáki, G. Distinct representations and theta dynamics in dorsal and ventral hippocampus. J. Neurosci. 30, 1777–1787 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ruediger, S., Spirig, D., Donato, F. & Caroni, P. Goal-oriented searching mediated by ventral hippocampus early in trial-and-error learning. Nature Neurosci. 15, 1563–1571 (2012).

    CAS  PubMed  Google Scholar 

  126. Viard, A., Doeller, C. F., Hartley, T., Bird, C. M. & Burgess, N. Anterior hippocampus and goal-directed spatial decision making. J. Neurosci. 31, 4613–4621 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mogenson, G. J., Jones, D. L. & Yim, C. Y. From motivation to action: functional interface between the limbic system and the motor system. Prog. Neurobiol. 14, 69–97 (1980).

    CAS  PubMed  Google Scholar 

  128. Pennartz, C., Ito, R., Verschure, P., Battaglia, F. & Robbins, T. The hippocampal–striatal axis in learning, prediction and goal-directed behavior. Trends Neurosci. 34, 548–559 (2011).

    CAS  PubMed  Google Scholar 

  129. 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 

  130. Lepage, M., Habib, R. & Tulving, E. Hippocampal PET activations of memory encoding and retrieval: the HIPER model. Hippocampus 8, 313–322 (1998).

    CAS  PubMed  Google Scholar 

  131. Schacter, D. L. & Wagner, A. D. Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus 9, 7–24 (1999).

    CAS  PubMed  Google Scholar 

  132. Daselaar, S. M., Fleck, M. S. & Cabeza, R. Triple dissociation in the medial temporal lobes: recollection, familiarity, and novelty. J. Neurophysiol. 96, 1902–1911 (2006).

    CAS  PubMed  Google Scholar 

  133. Kohler, S., Crane, J. & Milner, B. Differential contributions of the parahippocampal place area and the anterior hippocampus to human memory for scenes. Hippocampus 12, 718–723 (2002).

    PubMed  Google Scholar 

  134. Duzel, E. et al. Human hippocampal and parahippocampal activity during visual associative recognition memory for spatial and nonspatial stimulus configurations. J. Neurosci. 23, 9439–9444 (2003).

    PubMed  PubMed Central  Google Scholar 

  135. Kirchhoff, B. A., Wagner, A. D., Maril, A. & Stern, C. E. Prefrontal-temporal circuitry for episodic encoding and subsequent memory. J. Neurosci. 20, 6173–6180 (2000).

    CAS  PubMed  Google Scholar 

  136. Ranganath, C. & Rainer, G. Neural mechanisms for detecting and remembering novel events. Nature Rev. Neurosci. 4, 193–202 (2003).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  138. McNaughton, B. L. & Morris, R. G. Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci. 10, 408–415 (1987).

    Google Scholar 

  139. Paulsen, O. & Moser, E. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 21, 273–278 (1998).

    CAS  PubMed  Google Scholar 

  140. Hasselmo, M. E., Bodelón, C. & Wyble, B. P. A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Comput. 14, 793–817 (2002).

    PubMed  Google Scholar 

  141. 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).

    CAS  PubMed  Google Scholar 

  142. Poppenk, J., Evensmoen, H. R., Moscovitch, M. & Nadel, L. Long-axis specialization of the human hippocampus. Trends Cogn. Sci. 17, 230–240 (2013).

    PubMed  Google Scholar 

  143. Hirshhorn, M., Grady, C., Shayna Rosenbaum, R., Winocur, G. & Moscovitch, M. Brain regions involved in the retrieval of spatial and episodic details associated with a familiar environment: an fMRI study. Neuropsychologia 50, 3094–3106 (2012).

    PubMed  Google Scholar 

  144. Addis, D. R., Moscovitch, M., Crawley, A. P. & McAndrews, M. P. Recollective qualities modulate hippocampal activation during autobiographical memory retrieval. Hippocampus 14, 752–762 (2004).

    PubMed  Google Scholar 

  145. Chua, E. F., Schacter, D. L., Rand–Giovannetti, E. & Sperling, R. A. Evidence for a specific role of the anterior hippocampal region in successful associative encoding. Hippocampus 17, 1071–1080 (2007).

    PubMed  Google Scholar 

  146. Davachi, L. Item, context and relational episodic encoding in humans. Curr. Opin. Neurobiol. 16, 693–700 (2006).

    CAS  PubMed  Google Scholar 

  147. Giovanello, K. S., Schnyer, D. & Verfaellie, M. Distinct hippocampal regions make unique contributions to relational memory. Hippocampus 19, 111–117 (2009).

    PubMed  PubMed Central  Google Scholar 

  148. Cohen, N. J. & Eichenbaum, H. Memory, Amnesia, and the Hippocampal System (MIT Press, 1993).

    Google Scholar 

  149. Bunsey, M. & Eichenbaum, H. Conservation of hippocampal memory function in rats and humans. Nature 379, 255–257 (1996). This important rodent lesion study extended the hippocampal role in spatial memory to a non-spatial task — transitive inference — that can also be studied in humans.

    CAS  PubMed  Google Scholar 

  150. Heckers, S., Zalesak, M., Weiss, A. P., Ditman, T. & Titone, D. Hippocampal activation during transitive inference in humans. Hippocampus 14, 153–162 (2004).

    PubMed  Google Scholar 

  151. Preston, A. R., Shrager, Y., Dudukovic, N. M. & Gabrieli, J. D. E. Hippocampal contribution to the novel use of relational information in declarative memory. Hippocampus 14, 148–152 (2004).

    PubMed  Google Scholar 

  152. Eichenbaum, H. Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44, 109–120 (2004).

    CAS  PubMed  Google Scholar 

  153. Komorowski, R. W. et al. Ventral hippocampal neurons are shaped by experience to represent behaviorally relevant contexts. J. Neurosci. 33, 8079–8087 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Geisler, C. et al. Temporal delays among place cells determine the frequency of population theta oscillations in the hippocampus. Proc. Natl Acad. Sci. USA 107, 7957–7962 (2010).

    CAS  PubMed  Google Scholar 

  155. O'Keefe, J. & Recce, M. L. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3, 317–330 (1993).

    CAS  PubMed  Google Scholar 

  156. 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).

    CAS  PubMed  Google Scholar 

  157. Buzsáki, G. Neural syntax: cell assemblies, synapsembles, and readers. Neuron 68, 362–385 (2010).

    PubMed  PubMed Central  Google Scholar 

  158. Geuze, E., Vermetten, E. & Bremner, J. D. MR-based in vivo hippocampal volumetrics: 2. findings in neuropsychiatric disorders. Mol. Psychiatry 10, 160–184 (2005).

    CAS  PubMed  Google Scholar 

  159. Geuze, E., Vermetten, E. & Bremner, J. D. MR-based in vivo hippocampal volumetrics: 1. review of methodologies currently employed. Mol. Psychiatry 10, 147–159 (2005).

    CAS  PubMed  Google Scholar 

  160. Small, S. A., Schobel, S. A., Buxton, R. B., Witter, M. P. & Barnes, C. A. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nature Rev. Neurosci. 12, 585–601 (2011).

    CAS  Google Scholar 

  161. Titone, D., Ditman, T., Holzman, P. S., Eichenbaum, H. & Levy, D. L. Transitive inference in schizophrenia: impairments in relational memory organization. Schizophr. Res. 68, 235–247 (2004).

    PubMed  Google Scholar 

  162. Ongur, D. et al. The neural basis of relational memory deficits in schizophrenia. Arch. Gen. Psychiatry 63, 356–365 (2006). Although this study does not report a double dissociation between anterior and posterior hippocampal responses, it links deficits in transitive inference to abnormal anterior hippocampal function in schizophrenia.

    PubMed  Google Scholar 

  163. Goldman, M., Marlow-O'Connor, M., Torres, I. & Carter, C. S. Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits. Schizophr. Res. 98, 247–255 (2008).

    PubMed  Google Scholar 

  164. Goldman, M. B. et al. Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients. Hippocampus 17, 554–562 (2007).

    CAS  PubMed  Google Scholar 

  165. Luchins, D. J., Nettles, K. W. & Goldman, M. B. Anterior medial temporal lobe volumes in polydipsic schizophrenic patients with and without hypo-osmolemia: a pilot study. Biol. Psychiatry 42, 767–770 (1997).

    CAS  PubMed  Google Scholar 

  166. Gallagher, B. B. Endocrine abnormalities in human temporal lobe epilepsy. Yale J. Biol. Med. 60, 93–97 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Herzog, A. G., Seibel, M. M., Schomer, D. L., Vaitukaitis, J. L. & Geschwind, N. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch. Neurol. 43, 341–346 (1986).

    CAS  PubMed  Google Scholar 

  168. Quigg, M., Kiely, J. M., Shneker, B., Veldhuis, J. D. & Bertram, E. H. Interictal and postictal alterations of pulsatile secretions of luteinizing hormone in temporal lobe epilepsy in men. Ann. Neurol. 51, 559–566 (2002).

    PubMed  Google Scholar 

  169. Kheirbek, M. A. et al. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77, 955–968 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Gloor, P. The Temporal Lobe and Limbic System (Oxford Univ. Press, 1997).

    Google Scholar 

  171. Insausti, R. Comparative anatomy of the entorhinal cortex and hippocampus in mammals. Hippocampus 3, 19–26 (1993).

    PubMed  Google Scholar 

  172. Frotscher, M. & Seress, L. in The Hippocampus Book (eds Andersen, P., Morris, R., Amaral, D., Bliss, T. & O'Keefe, J.) 115–132 (Oxford Univ. Press, 2007).

    Google Scholar 

  173. Macchi, G. The ontogenic development of the olfactory telencephalon in man. J. Comp. Neurol. 95, 245–305 (1951).

    CAS  PubMed  Google Scholar 

  174. Kier, E. L., Fulbright, R. K. & Bronen, R. A. Limbic lobe embryology and anatomy: dissection and MR of the medial surface of the fetal cerebral hemisphere. AJNR Am. J. Neuroradiol. 16, 1847–1853 (1995).

    CAS  PubMed  Google Scholar 

  175. Friedman, D. P., Aggleton, J. P. & Saunders, R. C. Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain. J. Comp. Neurol. 450, 345–365 (2002).

    PubMed  Google Scholar 

  176. Saunders, R. C. & Aggleton, J. P. Origin and topography of fibers contributing to the fornix in macaque monkeys. Hippocampus 17, 396–411 (2007).

    PubMed  Google Scholar 

  177. Aggleton, J. P. A description of the amygdalo-hippocampal interconnections in the macaque monkey. Exp. Brain Res. 64, 515–526 (1986).

    CAS  PubMed  Google Scholar 

  178. Witter, M. P., Van Hoesen, G. W. & Amaral, D. G. Topographical organization of the entorhinal projection to the dentate gyrus of the monkey. J. Neurosci. 9, 216–228 (1989).

    CAS  PubMed  Google Scholar 

  179. Mohedano-Moriano, A. et al. Topographical and laminar distribution of cortical input to the monkey entorhinal cortex. J. Anat. 211, 250–260 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Mohedano-Moriano, A. et al. Convergence of unimodal and polymodal sensory input to the entorhinal cortex in the fascicularis monkey. Neuroscience 151, 255–271 (2008).

    CAS  PubMed  Google Scholar 

  181. Aggleton, J. P. Multiple anatomical systems embedded within the primate medial temporal lobe: implications for hippocampal function. Neurosci. Biobehav. Rev. 36, 1579–1596 (2012).

    PubMed  Google Scholar 

  182. Aggleton, J. P., Wright, N. F., Vann, S. D. & Saunders, R. C. Medial temporal lobe projections to the retrosplenial cortex of the macaque monkey. Hippocampus 22, 1883–1900 (2012).

    PubMed  PubMed Central  Google Scholar 

  183. Canto, C. B., Wouterlood, F. G. & Witter, M. P. What does the anatomical organization of the entorhinal cortex tell us? Neural Plast. 2008, 381243 (2008).

    PubMed  PubMed Central  Google Scholar 

  184. Bragdon, A. C., Taylor, D. M. & Wilson, W. A. Potassium-induced epileptiform activity in area CA3 varies markedly along the septotemporal axis of the rat hippocampus. Brain Res. 378, 169–173 (1986).

    CAS  PubMed  Google Scholar 

  185. Engel J. Jr et al. Presurgical evaluation for partial epilepsy: relative contributions of chronic depth-electrode recordings versus FDG-PET and scalp-sphenoidal ictal EEG. Neurology 40, 1670–1677 (1990).

    PubMed  Google Scholar 

  186. Mouritzen Dam, A. Epilepsy and neuron loss in the hippocampus. Epilepsia 21, 617–629 (1980).

    Google Scholar 

  187. Babb, T. L. et al. Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia 25, 729–740 (1984).

    CAS  PubMed  Google Scholar 

  188. O'Connor, W. M. et al. Hippocampal cell distributions in temporal lobe epilepsy: a comparison between patients with and without an early risk factor. Epilepsia 37, 440–449 (1996).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  190. Sahay, A. & Hen, R. Adult hippocampal neurogenesis in depression. Nature Neurosci. 10, 1110–1115 (2007).

    CAS  PubMed  Google Scholar 

  191. Boldrini, M. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376–2389 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Lipska, B. K., Jaskiw, G. E. & Weinberger, D. R. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 9, 67–75 (1993).

    CAS  PubMed  Google Scholar 

  193. Benes, F. M., Sorensen, I. & Bird, E. D. Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr. Bull. 17, 597–608 (1991).

    CAS  PubMed  Google Scholar 

  194. Maller, J. J. et al. Hippocampal volumetrics in treatment-resistant depression and schizophrenia: the devil's in De-Tail. Hippocampus 22, 9–16 (2012).

    PubMed  Google Scholar 

  195. Ashton, D., Van Reempts, J., Haseldonckx, M. & Willems, R. Dorsal-ventral gradient in vulnerability of CA1 hippocampus to ischemia: a combined histological and electrophysiological study. Brain Res. 487, 368–372 (1989).

    CAS  PubMed  Google Scholar 

  196. Martens, U., Capito, B. & Wree, A. Septotemporal distribution of [3H]MK-801, [3H]AMPA and [3H]kainate binding sites in the rat hippocampus. Anat. Embryol. 198, 195–204 (1998).

    CAS  PubMed  Google Scholar 

  197. Rothman, S. M. & Olney, J. W. Excitotoxity and the NMDA receptor. Trends Neurosci. 10, 299–302 (1987).

    CAS  Google Scholar 

  198. Smith, M. L., Auer, R. N. & Siesjo, B. K. The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol. 64, 319–332 (1984).

    CAS  PubMed  Google Scholar 

  199. Horstmann, A. et al. Resuscitating the heart but losing the brain: brain atrophy in the aftermath of cardiac arrest. Neurology 74, 306–312 (2010).

    CAS  PubMed  Google Scholar 

  200. Zola-Morgan, S., Squire, L. R. & Amaral, D. G. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J. Neurosci. 6, 2950–2967 (1986).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank L. Giocomo for helpful discussion. B.A.S. is supported by the Spanish Ministry of Science and Innovation (SAF2011-27766) and Marie Curie Career Integration Grant (FP7-PEOPLE-2011-CIG 304248), E.IM. and M.P.W. are supported by the Kavli Foundation and Centre of Excellence grant from the Norwegian Research Council, and E.S.L. by the Allen Institute for Brain Science.

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Authors and Affiliations

  1. Laboratory for Clinical Neuroscience, Centre for Biomedical Technology, Technical University of Madrid, Campus de Montegancedo, Pozuelo de Alarcón, 28223, Spain

    Bryan A. Strange

  2. Department of Neuroimaging, Alzheimer's Disease Research Centre, Reina Sofia-CIEN Foundation, Calle Valderrebollo 5, Madrid, 28071, Spain

    Bryan A. Strange

  3. Kavli Institute for Systems Neuroscience and Centre for the Biology of Memory, MTFS, Olav Kyrres gate 9, Norwegian University of Science and Technology, Trondheim, NO-7489, Norway

    Menno P. Witter & Edvard I. Moser

  4. Allen Institute for Brain Science, Seattle, 98103, Washington, USA

    Ed S. Lein

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Supplementary information

Supplementary information S1 (box)

Long-axis neurotransmitter projection patterns in the rat (PDF 216 kb)

Supplementary information S2 (table)

Receptor distributions along the hippocampal long axis of, and example functional dichotomies associated with, different neurotransmitter systems (PDF 304 kb)

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Glossary

Hippocampus

In animal studies, the term describes dentate gyrus (DG) and CA subfields. In human functional MRI studies, the term typically includes the DG, CA subfields and subiculum (except in high-resolution functional MRI).

Episodic memory

Long-term memory for events or episodes that is accessible to conscious recollection.

Semantic memory

Long-term memory for facts that is accessible to conscious recollection.

Place cells

Pyramidal cells that fire in specific locations with spatially restricted firing patterns that are maintained on memory retention trials.

Callosal mammals

Mammals with a corpus callosum. In acallosal mammals, such as the opossum, the dorsal portion of the hippocampus extends into the frontal lobe.

Susceptibility artefact

The different magnetic susceptibility of air and tissue cause inhomogeneities in the magnetic resonance scanner's static magnetic field at the air–tissue boundaries. These inhomogeneities result in geometrical distortion and reduced sensitivity of functional images, particularly in the orbitofrontal cortex and anterior medial temporal lobe.

Hippocampal MRI unfolding

The application of cortical unfolding techniques to high-resolution magnetic resonance images of the hippocampus. Structural images are segmented and the grey matter surface is extracted and stretched until it is a two-dimensional, flat surface.

Transitive inference

If A is paired with B, and B paired with C, the transitive inference is A with C.

Theta rhythm

A prominent 4–10 Hz oscillation in the hippocampal local field potential. It is studied mostly in rodents but is also present in humans.

Phase precession

The phenomenon that when a rat first enters the field of firing of a place cell, spiking occurs at late phases but shifts to earlier theta phases as the rat moves through the place field.

Adult neurogenesis

The production of new neurons within the brain of an adult animal. Adult neurogenesis is primarily confined to the subventricular zone and the subgranular zone of the dentate gyrus.

Ischaemia

A restriction in blood supply, which leads to lack of oxygen delivery.

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Strange, B., Witter, M., Lein, E. et al. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci 15, 655–669 (2014). https://doi.org/10.1038/nrn3785

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