Review Article | Published:

Heterogeneity within classical cell types is the rule: lessons from hippocampal pyramidal neurons

Nature Reviews Neurosciencevolume 20pages193204 (2019) | Download Citation

Abstract

The mechanistic operation of brain regions is often interpreted by partitioning constituent neurons into ‘cell types’. Historically, such cell types were broadly defined by their correspondence to gross features of the nervous system (such as cytoarchitecture). Modern-day neuroscientific techniques, enabling a more nuanced examination of neuronal properties, have illustrated a wealth of heterogeneity within these classical cell types. Here, we review the extent of this within-cell-type heterogeneity in one of the simplest cortical regions of the mammalian brain, the rodent hippocampus. We focus on the mounting evidence that the classical CA3, CA1 and subiculum pyramidal cell types all exhibit prominent and spatially patterned within-cell-type heterogeneity, and suggest these cell types provide a model system for exploring the organization and function of such heterogeneity. Given that the hippocampus is structurally simple and evolutionarily ancient, within-cell-type heterogeneity is likely to be a general and crucial feature of the mammalian brain.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Eccles, J. C., Ito, M. & Szentágothai, J. N. The Cerebellum as a Neuronal Machine (Springer-Verlag, 1967).

  2. 2.

    Ramón y Cajal, S. Histologie du Système Nerveux de l’homme & des Vertébreés (Oxford Univ. Press, 1911).

  3. 3.

    de No, R. L. Studies on the structure of the cerebral cortex XI continuation of the study of the ammonic system. J. Psychol. Neurol. 46, 113–177 (1934).

  4. 4.

    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).

  5. 5.

    Aronov, D., Nevers, R. & Tank, D. W. Mapping of a non-spatial dimension by the hippocampal-entorhinal circuit. Nature 543, 719–722 (2017).

  6. 6.

    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).

  7. 7.

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

  8. 8.

    Jimenez, J. C. et al. Anxiety cells in a hippocampal-hypothalamic circuit. Neuron 97, 670–683 (2018).

  9. 9.

    Ciocchi, S., Passecker, J., Malagon-Vina, H., Mikus, N. & Klausberger, T. Selective information routing by ventral hippocampal CA1 projection neurons. Science 348, 560–563 (2015). Combining antidromic stimulation with recording, this study finds that ventral CA1 cells exhibit pronounced heterogeneity in their feature selectivity, and this heterogeneity correlates with their downstream targets.

  10. 10.

    Xu, C. et al. Distinct hippocampal pathways mediate dissociable roles of context in memory retrieval. Cell 167, 961–972 (2016).

  11. 11.

    Floriou-Servou, A. et al. Distinct proteomic, transcriptomic, and epigenetic stress responses in dorsal and ventral hippocampus. Biol. Psychiatry 84, 531–541 (2018).

  12. 12.

    Thompson, C. L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008). This pioneering study examines transcriptomic heterogeneity across the spatial extent of CA3, identifying multiple discrete subdomains of CA3 pyramidal cells that vary markedly in expression of functionally relevant genes.

  13. 13.

    Cembrowski, M. S. et al. Dissociable structural and functional hippocampal outputs via distinct subiculum cell classes. Cell 173, 1280–1292 (2018). This study coherently maps heterogeneity across molecules, cells, circuits and behaviour within the subiculum pyramidal cell population, revealing two distinct streams of subiculum output.

  14. 14.

    Cembrowski, M. S. et al. Spatial gene-expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons. Neuron 89, 351–368 (2016). This study performs next-generation RNA sequencing of CA1 pyramidal cells across dorsal–ventral, proximal–distal and superficial–deep axes, identifying marked continuous heterogeneity along all three axes.

  15. 15.

    Bienkowski, M. S. et al. Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks. Nat. Neurosci. 21, 1628–1643 (2018).

  16. 16.

    Aggleton, J. P. & Christiansen, K. in The Connected Hippocampus Vol. 219 (eds O’Mara, S. & Tsanov, M.) 65–82 (Elsevier, 2015).

  17. 17.

    Strange, B. A., Witter, M. P., Lein, E. S. & Moser, E. I. Functional organization of the hippocampal longitudinal axis. Nat. Rev. Neurosci. 15, 655–669 (2014).

  18. 18.

    Strange, B. A., Fletcher, P. C., Henson, R. N., Friston, K. J. & Dolan, R. J. Segregating the functions of human hippocampus. Proc. Natl Acad. Sci. USA 96, 4034–4039 (1999).

  19. 19.

    Collin, S. H., Milivojevic, B. & Doeller, C. F. Memory hierarchies map onto the hippocampal long axis in humans. Nat. Neurosci. 18, 1562–1564 (2015).

  20. 20.

    Ding, S. L. Comparative anatomy of the prosubiculum, subiculum, presubiculum, postsubiculum, and parasubiculum in human, monkey, and rodent. J. Comp. Neurol. 521, 4145–4162 (2013).

  21. 21.

    Chawla, M. K., Sutherland, V. L., Olson, K., McNaughton, B. L. & Barnes, C. A. Behavior-driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus. Hippocampus 28, 178–185 (2018).

  22. 22.

    Larimer, P. & Strowbridge, B. W. Representing information in cell assemblies: persistent activity mediated by semilunar granule cells. Nat. Neurosci. 13, 213–222 (2010).

  23. 23.

    Williams, P. A., Larimer, P., Gao, Y. & Strowbridge, B. W. Semilunar granule cells: glutamatergic neurons in the rat dentate gyrus with axon collaterals in the inner molecular layer. J. Neurosci. 27, 13756–13761 (2007).

  24. 24.

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

  25. 25.

    Cembrowski, M. S., Wang, L., Sugino, K., Shields, B. C. & Spruston, N. Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons. eLife 5, e14997 (2016).

  26. 26.

    Scharfman, H. E., Sollas, A. L., Smith, K. L., Jackson, M. B. & Goodman, J. H. Structural and functional asymmetry in the normal and epileptic rat dentate gyrus. J. Comp. Neurol. 454, 424–439 (2002).

  27. 27.

    Guenthner, C. J., Miyamichi, K., Yang, H. H., Heller, H. C. & Luo, L. Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations. Neuron 78, 773–784 (2013).

  28. 28.

    Chawla, M. K. et al. Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience. Hippocampus 15, 579–586 (2005).

  29. 29.

    Harris, K. D. et al. Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLOS Biol. 16, e2006387 (2018).

  30. 30.

    Donato, F., Chowdhury, A., Lahr, M. & Caroni, P. Early- and late-born parvalbumin basket cell subpopulations exhibiting distinct regulation and roles in learning. Neuron 85, 770–786 (2015).

  31. 31.

    Lee, S. H. et al. Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells. Neuron 82, 1129–1144 (2014).

  32. 32.

    Bohm, C. et al. Functional diversity of subicular principal cells during hippocampal ripples. J. Neurosci. 35, 13608–13618 (2015). This study demonstrates differential recruitment of regular spiking and bursting subiculum neurons during sharp wave ripples in awake mice and that these electrical phenotypes are wired into different subnetworks.

  33. 33.

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

  34. 34.

    Slomianka, L., Amrein, I., Knuesel, I., Sorensen, J. C. & Wolfer, D. P. Hippocampal pyramidal cells: the reemergence of cortical lamination. Brain Struct. Funct. 216, 301–317 (2011).

  35. 35.

    Igarashi, K. M., Ito, H. T., Moser, E. I. & Moser, M. B. Functional diversity along the transverse axis of hippocampal area CA1. FEBS Lett. 588, 2470–2476 (2014).

  36. 36.

    Soltesz, I. & Losonczy, A. CA1 pyramidal cell diversity enabling parallel information processing in the hippocampus. Nat. Neurosci. 21, 484–493 (2018).

  37. 37.

    Knierim, J. J., Lee, I. & Hargreaves, E. L. Hippocampal place cells: parallel input streams, subregional processing, and implications for episodic memory. Hippocampus 16, 755–764 (2006).

  38. 38.

    Knierim, J. J., Neunuebel, J. P. & Deshmukh, S. S. Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Phil. Trans. R. Soc. B 369, 20130369 (2014).

  39. 39.

    Bohm, C., Peng, Y., Geiger, J. R. P. & Schmitz, D. Routes to, from and within the subiculum. Cell Tissue Res. 373, 557–563 (2018).

  40. 40.

    Witter, M. P. Connections of the subiculum of the rat: topography in relation to columnar and laminar organization. Behav. Brain Res. 174, 251–264 (2006).

  41. 41.

    Witter, M. P. Intrinsic and extrinsic wiring of CA3: indications for connectional heterogeneity. Learn. Mem. 14, 705–713 (2007).

  42. 42.

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

  43. 43.

    Valero, M. & de la Prida, L. M. The hippocampus in depth: a sublayer-specific perspective of entorhinal-hippocampal function. Curr. Opin. Neurobiol. 52, 107–114 (2018).

  44. 44.

    Mallory, C. S. & Giocomo, L. M. Heterogeneity in hippocampal place coding. Curr. Opin. Neurobiol. 49, 158–167 (2018).

  45. 45.

    O’Mara, S. M., Sanchez-Vives, M. V., Brotons-Mas, J. R. & O’Hare, E. Roles for the subiculum in spatial information processing, memory, motivation and the temporal control of behaviour. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 782–790 (2009).

  46. 46.

    Geiller, T., Royer, S. & Choi, J. S. Segregated cell populations enable distinct parallel encoding within the radial axis of the CA1 pyramidal layer. Exp. Neurobiol. 26, 1–10 (2017).

  47. 47.

    Sauvage, M. M., Nakamura, N. H. & Beer, Z. Mapping memory function in the medial temporal lobe with the immediate-early gene Arc. Behav. Brain Res. 254, 22–33 (2013).

  48. 48.

    Masurkar, A. V. Towards a circuit-level understanding of hippocampal CA1 dysfunction in Alzheimer’s disease across anatomical axes. J. Alzheimers Dis. Parkinsonism 8, 412 (2018).

  49. 49.

    Kesner, R. P. A process analysis of the CA3 subregion of the hippocampus. Front. Cell Neurosci. 7, 78 (2013).

  50. 50.

    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).

  51. 51.

    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).

  52. 52.

    Masukawa, L. M., Benardo, L. S. & Prince, D. A. Variations in electrophysiological properties of hippocampal neurons in different subfields. Brain Res. 242, 341–344 (1982).

  53. 53.

    Guzman, S. J., Schlogl, A., Frotscher, M. & Jonas, P. Synaptic mechanisms of pattern completion in the hippocampal CA3 network. Science 353, 1117–1123 (2016).

  54. 54.

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

  55. 55.

    Lee, H., Wang, C., Deshmukh, S. S. & Knierim, J. J. Neural population evidence of functional heterogeneity along the CA3 transverse axis: pattern completion versus pattern separation. Neuron 87, 1093–1105 (2015).

  56. 56.

    Lu, L., Igarashi, K. M., Witter, M. P., Moser, E. I. & Moser, M. B. Topography of place maps along the CA3-to-CA2 axis of the hippocampus. Neuron 87, 1078–1092 (2015).

  57. 57.

    Sun, Q. et al. Proximodistal heterogeneity of hippocampal CA3 pyramidal neuron intrinsic properties, connectivity, and reactivation during memory recall. Neuron 95, 656–672 (2017). The authors examine heterogeneity across the CA3 proximal–distal axis using a range of complementary experimental techniques. This tour de force shows that CA3 pyramidal cell heterogeneity is largely graded and spans intrinsic electrical properties, synaptic connectivity and reactivation induced by memory recall.

  58. 58.

    Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008).

  59. 59.

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

  60. 60.

    Hunt, D. L., Linaro, D., Si, B., Romani, S. & Spruston, N. A novel pyramidal cell type promotes sharp-wave synchronization in the hippocampus. Nat. Neurosci. 21, 985–995 (2018).

  61. 61.

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

  62. 62.

    Andersen, P. The Hippocampus Book (Oxford Univ. Press, 2007).

  63. 63.

    Tamamaki, N. & Nojyo, Y. Preservation of topography in the connections between the subiculum, field CA1, and the entorhinal cortex in rats. J. Comp. Neurol. 353, 379–390 (1995).

  64. 64.

    Hargreaves, E. L., Rao, G., Lee, I. & Knierim, J. J. Major dissociation between medial and lateral entorhinal input to dorsal hippocampus. Science 308, 1792–1794 (2005). This study shows that neurons in the medial and lateral entorhinal cortex show prominent and minimal spatial modulation, respectively, demonstrating a dissociation between spatial and non-spatial inputs to the hippocampus.

  65. 65.

    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).

  66. 66.

    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).

  67. 67.

    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).

  68. 68.

    Giocomo, L. M. et al. Topography of head direction cells in medial entorhinal cortex. Curr. Biol. 24, 252–262 (2014).

  69. 69.

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

  70. 70.

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

  71. 71.

    Nakazawa, Y., Pevzner, A., Tanaka, K. Z. & Wiltgen, B. J. Memory retrieval along the proximodistal axis of CA1. Hippocampus 26, 1140–1148 (2016).

  72. 72.

    Hartzell, A. L. et al. Transcription of the immediate-early gene Arc in CA1 of the hippocampus reveals activity differences along the proximodistal axis that are attenuated by advanced age. J. Neurosci. 33, 3424–3433 (2013).

  73. 73.

    Ito, H. T. & Schuman, E. M. Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs. Hippocampus 22, 372–387 (2012).

  74. 74.

    Igarashi, K. M., Lu, L., Colgin, L. L., Moser, M. B. & Moser, E. I. Coordination of entorhinal-hippocampal ensemble activity during associative learning. Nature 510, 143–147 (2014).

  75. 75.

    Cenquizca, L. A. & Swanson, L. W. Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res. Rev. 56, 1–26 (2007).

  76. 76.

    Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

  77. 77.

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

  78. 78.

    Pikkarainen, M., Ronkko, S., Savander, V., Insausti, R. & Pitkanen, 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).

  79. 79.

    Pitkanen, 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).

  80. 80.

    Hunsaker, M. R., Fieldsted, P. M., Rosenberg, J. S. & Kesner, R. P. Dissociating the roles of dorsal and ventral CA1 for the temporal processing of spatial locations, visual objects, and odors. Behav. Neurosci. 122, 643–650 (2008).

  81. 81.

    Kesner, R. P., Hunsaker, M. R. & Ziegler, W. The role of the dorsal CA1 and ventral CA1 in memory for the temporal order of a sequence of odors. Neurobiol. Learn. Mem. 93, 111–116 (2010).

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

    Malik, R., Dougherty, K. A., Parikh, K., Byrne, C. & Johnston, D. Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis. Hippocampus 26, 341–361 (2016).

  85. 85.

    Mizuseki, K., Diba, K., Pastalkova, E. & Buzsaki, G. Hippocampal CA1 pyramidal cells form functionally distinct sublayers. Nat. Neurosci. 14, 1174–1181 (2011). This work shows that across the radial axis, CA1 pyramidal cells in vivo can exhibit heterogeneity in firing rate, bursting, place field propensity and sleep-associated modulation.

  86. 86.

    Valero, M. et al. Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples. Nat. Neurosci. 18, 1281–1290 (2015).

  87. 87.

    Masurkar, A. V. et al. Medial and lateral entorhinal cortex differentially excite deep versus superficial CA1 pyramidal neurons. Cell Rep. 18, 148–160 (2017).

  88. 88.

    Geiller, T., Fattahi, M., Choi, J. S. & Royer, S. Place cells are more strongly tied to landmarks in deep than in superficial CA1. Nat. Commun. 8, 14531 (2017).

  89. 89.

    Danielson, N. B. et al. Sublayer-specific coding dynamics during spatial navigation and learning in hippocampal area CA1. Neuron 91, 652–665 (2016). This study uses simultaneous imaging of CA1 superficial and deep layers in awake, behaving mice to identify heterogeneity between stability and flexibility of representations.

  90. 90.

    Habib, N. et al. Div-Seq: single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons. Science 353, 925–928 (2016).

  91. 91.

    Milior, G. et al. Electrophysiological properties of CA1 pyramidal neurons along the longitudinal axis of the mouse hippocampus. Sci. Rep. 6, 38242 (2016).

  92. 92.

    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).

  93. 93.

    Amaral, D. G., Dolorfo, C. & Alvarez-Royo, P. Organization of CA1 projections to the subiculum: a PHA-L analysis in the rat. Hippocampus 1, 415–435 (1991).

  94. 94.

    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).

  95. 95.

    Naber, P. A. & Witter, M. P. Subicular efferents are organized mostly as parallel projections: a double-labeling, retrograde-tracing study in the rat. J. Comp. Neurol. 393, 284–297 (1998).

  96. 96.

    Kinnavane, L., Vann, S. D., Nelson, A. J. D., O’Mara, S. M. & Aggleton, J. P. Collateral projections innervate the mammillary bodies and retrosplenial cortex: a new category of hippocampal cells. eNeuro. https://doi.org/10.1523/ENEURO.0383-17.2018 (2018).

  97. 97.

    Graves, A. R. et al. Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors. Neuron 76, 776–789 (2012).

  98. 98.

    Jarsky, T., Mady, R., Kennedy, B. & Spruston, N. Distribution of bursting neurons in the CA1 region and the subiculum of the rat hippocampus. J. Comp. Neurol. 506, 535–547 (2008).

  99. 99.

    Greene, J. R. & Totterdell, S. Morphology and distribution of electrophysiologically defined classes of pyramidal and nonpyramidal neurons in rat ventral subiculum in vitro. J. Comp. Neurol. 380, 395–408 (1997).

  100. 100.

    Staff, N. P., Jung, H. Y., Thiagarajan, T., Yao, M. & Spruston, N. Resting and active properties of pyramidal neurons in subiculum and CA1 of rat hippocampus. J. Neurophysiol. 84, 2398–2408 (2000).

  101. 101.

    Eller, J., Zarnadze, S., Bauerle, P., Dugladze, T. & Gloveli, T. Cell type-specific separation of subicular principal neurons during network activities. PLOS ONE 10, e0123636 (2015).

  102. 102.

    Wozny, C. et al. VGLUT2 functions as a differential marker for hippocampal output neurons. Front. Cell Neurosci. 12, 337 (2018).

  103. 103.

    Yamawaki, N., Corcoran, K. A., Guedea, A. L., Shepherd, G. M. G. & Radulovic, J. Differential contributions of glutamatergic hippocampal–retrosplenial cortical projections to the formation and persistence of context memories. Cereb. Cortex. https://doi.org/10.1093/cercor/bhy142 (2018).

  104. 104.

    Kim, Y. & Spruston, N. Target-specific output patterns are predicted by the distribution of regular-spiking and bursting pyramidal neurons in the subiculum. Hippocampus 22, 693–706 (2011).

  105. 105.

    Graves, A. R., Moore, S. J., Spruston, N., Tryba, A. K. & Kaczorowski, C. C. Brain-derived neurotrophic factor differentially modulates excitability of two classes of hippocampal output neurons. J. Neurophysiol. 116, 466–471 (2016).

  106. 106.

    Kloosterman, F., Witter, M. P. & Van Haeften, T. Topographical and laminar organization of subicular projections to the parahippocampal region of the rat. J. Comp. Neurol. 455, 156–171 (2003).

  107. 107.

    Ishizuka, N. Laminar organization of the pyramidal cell layer of the subiculum in the rat. J. Comp. Neurol. 435, 89–110 (2001).

  108. 108.

    Honda, Y. & Ishizuka, N. Topographic distribution of cortical projection cells in the rat subiculum. Neurosci. Res. 92, 1–20 (2015).

  109. 109.

    Ishihara, Y. & Fukuda, T. Immunohistochemical investigation of the internal structure of the mouse subiculum. Neuroscience 337, 242–266 (2016).

  110. 110.

    Cembrowski, M. S. et al. The subiculum is a patchwork of discrete subregions. eLife 7, e37701 (2018).

  111. 111.

    Gangarossa, G. et al. Spatial distribution of D1R- and D2R-expressing medium-sized spiny neurons differs along the rostro-caudal axis of the mouse dorsal striatum. Front. Neural Circuits 7, 124 (2013).

  112. 112.

    Cembrowski, M. S. & Spruston, N. Integrating results across methodologies is essential for producing robust neuronal taxonomies. Neuron 94, 747–751 (2017).

  113. 113.

    Okuyama, T., Kitamura, T., Roy, D. S., Itohara, S. & Tonegawa, S. Ventral CA1 neurons store social memory. Science 353, 1536–1541 (2016).

  114. 114.

    Padilla-Coreano, N. et al. Direct ventral hippocampal-prefrontal input is required for anxiety-related neural activity and behavior. Neuron 89, 857–866 (2016).

  115. 115.

    Witharana, W. K. et al. Nonuniform allocation of hippocampal neurons to place fields across all hippocampal subfields. Hippocampus 26, 1328–1344 (2016).

  116. 116.

    Wickersham, I. R., Sullivan, H. A. & Seung, H. S. Production of glycoprotein-deleted rabies viruses for monosynaptic tracing and high-level gene expression in neurons. Nat. Protoc. 5, 595–606 (2010).

  117. 117.

    Reardon, T. R. et al. Rabies virus CVS-N2c(DeltaG) strain enhances retrograde synaptic transfer and neuronal viability. Neuron 89, 711–724 (2016).

  118. 118.

    Berns, D. S., DeNardo, L. A., Pederick, D. T. & Luo, L. Teneurin-3 controls topographic circuit assembly in the hippocampus. Nature 554, 328–333 (2018). This paper shows that teneurin 3 is selectively expressed in distinct proximal–distal subregions of CA1 and the subiculum and in the medial entorhinal cortex.

  119. 119.

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

  120. 120.

    Goaillard, J. M., Taylor, A. L., Schulz, D. J. & Marder, E. Functional consequences of animal-to-animal variation in circuit parameters. Nat. Neurosci. 12, 1424–1430 (2009).

  121. 121.

    Prinz, A. A., Bucher, D. & Marder, E. Similar network activity from disparate circuit parameters. Nat. Neurosci. 7, 1345–1352 (2004).

  122. 122.

    Dueck, H., Eberwine, J. & Kim, J. Variation is function: are single cell differences functionally important?: Testing the hypothesis that single cell variation is required for aggregate function. Bioessays 38, 172–180 (2016).

  123. 123.

    Cembrowski, M. S. & Menon, V. Continuous variation within cell types of the nervous system. Trends Neurosci. 41, 337–348 (2018).

  124. 124.

    Kay, K. et al. A hippocampal network for spatial coding during immobility and sleep. Nature 531, 185–190 (2016).

  125. 125.

    Fernandez-Lamo, I. et al. Proximodistal organization of the CA2 hippocampal area. Preprint at bioRxiv https://doi.org/10.1101/331025 (2018).

  126. 126.

    Oliva, A., Fernandez-Ruiz, A., Buzsaki, G. & Berenyi, A. Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions. Hippocampus 26, 1593–1607 (2016).

  127. 127.

    Shinohara, Y. et al. Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc. Natl Acad. Sci. USA 105, 19498–19503 (2008).

  128. 128.

    Shipton, O. A. et al. Left-right dissociation of hippocampal memory processes in mice. Proc. Natl Acad. Sci. USA 111, 15238–15243 (2014).

  129. 129.

    Ramsden, H. L., Surmeli, G., McDonagh, S. G. & Nolan, M. F. Laminar and dorsoventral molecular organization of the medial entorhinal cortex revealed by large-scale anatomical analysis of gene expression. PLOS Comput. Biol. 11, e1004032 (2015).

  130. 130.

    Surmeli, G. et al. Molecularly defined circuitry reveals input-output segregation in deep layers of the medial entorhinal cortex. Neuron 88, 1040–1053 (2015).

  131. 131.

    Tasic, B. et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat. Neurosci. 19, 335–346 (2016).

  132. 132.

    Economo, M. N. et al. Distinct descending motor cortex pathways and their roles in movement. Nature 563, 79–84 (2018).

  133. 133.

    Sorensen, S. A. et al. Correlated gene expression and target specificity demonstrate excitatory projection neuron diversity. Cereb. Cortex 25, 433–449 (2015).

  134. 134.

    Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014).

  135. 135.

    Gokce, O. et al. Cellular taxonomy of the mouse striatum as revealed by single-cell RNA-Seq. Cell Rep. 16, 1126–1137 (2016).

  136. 136.

    Beyeler, A. et al. Organization of valence-encoding and projection-defined neurons in the basolateral amygdala. Cell Rep. 22, 905–918 (2018).

  137. 137.

    Chen, R., Wu, X., Jiang, L. & Zhang, Y. Single-cell RNA-Seq reveals hypothalamic cell diversity. Cell Rep. 18, 3227–3241 (2017).

  138. 138.

    Phillips, J. et al. A single spectrum of neuronal identities across thalamus. Preprint at bioRxiv https://doi.org/10.1101/241315 (2017).

  139. 139.

    Geschwind, D. H. & Rakic, P. Cortical evolution: judge the brain by its cover. Neuron 80, 633–647 (2013).

  140. 140.

    Miller, J. A., Horvath, S. & Geschwind, D. H. Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc. Natl Acad. Sci. USA 107, 12698–12703 (2010).

  141. 141.

    Zeisel, A. et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138–1142 (2015).

  142. 142.

    Rudy, B., Fishell, G., Lee, S. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61 (2011).

  143. 143.

    Lau, C. et al. Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain. BMC Bioinformatics 9, 153 (2008).

  144. 144.

    Gonzales, R. B., DeLeon Galvan, C. J., Rangel, Y. M. & Claiborne, B. J. Distribution of thorny excrescences on CA3 pyramidal neurons in the rat hippocampus. J. Comp. Neurol. 430, 357–368 (2001).

  145. 145.

    Golding, N. L., Mickus, T. J., Katz, Y., Kath, W. L. & Spruston, N. Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites. J. Physiol. 568, 69–82 (2005).

  146. 146.

    Tervo, D. G. et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 92, 372–382 (2016).

  147. 147.

    Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007).

  148. 148.

    Arszovszki, A., Borhegyi, Z. & Klausberger, T. Three axonal projection routes of individual pyramidal cells in the ventral CA1 hippocampus. Front. Neuroanat. 8, 53 (2014).

  149. 149.

    Betley, J. N., Cao, Z. F., Ritola, K. D. & Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350 (2013).

  150. 150.

    Leonardo, E. D., Richardson-Jones, J. W., Sibille, E., Kottman, A. & Hen, R. Molecular heterogeneity along the dorsal-ventral axis of the murine hippocampal CA1 field: a microarray analysis of gene expression. Neuroscience 137, 177–186 (2006).

  151. 151.

    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).

  152. 152.

    Baimbridge, K. G. & Miller, J. J. Immunohistochemical localization of calcium-binding protein in the cerebellum, hippocampal formation and olfactory bulb of the rat. Brain Res. 245, 223–229 (1982).

  153. 153.

    Slomianka, L. & Geneser, F. A. Distribution of acetylcholinesterase in the hippocampal region of the mouse: II. Subiculum and hippocampus. J. Comp. Neurol. 312, 525–536 (1991).

  154. 154.

    Bilkey, D. K. & Schwartzkroin, P. A. Variation in electrophysiology and morphology of hippocampal CA3 pyramidal cells. Brain Res. 514, 77–83 (1990).

  155. 155.

    Dougherty, K. A. 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).

  156. 156.

    Maroso, M. et al. Cannabinoid control of learning and memory through HCN channels. Neuron 89, 1059–1073 (2016).

  157. 157.

    Thome, C. et al. Axon-carrying dendrites convey privileged synaptic input in hippocampal neurons. Neuron 83, 1418–1430 (2014).

  158. 158.

    Li, Y. et al. A distinct entorhinal cortex to hippocampal CA1 direct circuit for olfactory associative learning. Nat. Neurosci. 20, 559–570 (2017).

  159. 159.

    Bannister, N. J. & Larkman, A. U. Dendritic morphology of CA1 pyramidal neurones from the rat hippocampus: I. Branching patterns. J. Comp. Neurol. 360, 150–160 (1995).

  160. 160.

    Fattahi, M., Sharif, F., Geiller, T. & Royer, S. Differential representation of landmark and self-motion information along the CA1 radial axis: self-motion generated place fields shift toward landmarks during septal inactivation. J. Neurosci. 38, 6766–6778 (2018).

  161. 161.

    Andrzejewski, M. E., Spencer, R. C. & Kelley, A. E. Dissociating ventral and dorsal subicular dopamine D1 receptor involvement in instrumental learning, spontaneous motor behavior, and motivation. Behav. Neurosci. 120, 542–553 (2006).

  162. 162.

    Kim, S. M., Ganguli, S. & Frank, L. M. Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum. J. Neurosci. 32, 11539–11558 (2012).

  163. 163.

    Beer, Z., Chwiesko, C. & Sauvage, M. M. Processing of spatial and non-spatial information reveals functional homogeneity along the dorso-ventral axis of CA3, but not CA1. Neurobiol. Learn. Mem. 111, 56–64 (2014).

  164. 164.

    Nakamura, N. H., Flasbeck, V., Maingret, N., Kitsukawa, T. & Sauvage, M. M. Proximodistal segregation of nonspatial information in CA3: preferential recruitment of a proximal CA3-distal CA1 network in nonspatial recognition memory. J. Neurosci. 33, 11506–11514 (2013).

  165. 165.

    Flasbeck, V., Atucha, E., Nakamura, N. H., Yoshida, M. & Sauvage, M. M. Spatial information is preferentially processed by the distal part of CA3: implication for memory retrieval. Behav. Brain Res. 347, 116–123 (2018).

  166. 166.

    Beer, Z. et al. The memory for time and space differentially engages the proximal and distal parts of the hippocampal subfields CA1 and CA3. PLOS Biol. 16, e2006100 (2018).

  167. 167.

    Hunsaker, M. R. & Kesner, R. P. Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear. Neurobiol. Learn. Mem. 89, 61–69 (2008).

  168. 168.

    Hunsaker, M. R., Rosenberg, J. S. & Kesner, R. P. The role of the dentate gyrus, CA3a, b, and CA3c for detecting spatial and environmental novelty. Hippocampus 18, 1064–1073 (2008).

Download references

Acknowledgements

The authors thank E. Bloss and V. Menon for helpful discussions.

Reviewer information

Nature Reviews Neuroscience thanks A. Losonczy, and other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

Affiliations

  1. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA

    • Mark S. Cembrowski
    •  & Nelson Spruston

Authors

  1. Search for Mark S. Cembrowski in:

  2. Search for Nelson Spruston in:

Contributions

M.S.C. researched the data for the article. M.S.C. and N.S. made substantial contributions to the content of the article, wrote the article and reviewed and/or edited the article before submission.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Mark S. Cembrowski or Nelson Spruston.

Glossary

Pattern completion

An operation that allows population activity to converge to a stored pattern despite incomplete or noisy input. In the hippocampus, this operation is classically attributed to CA3 pyramidal cells owing to their recurrent connectivity.

Place fields

The spatial domains in which cells show increased activity, as assayed through in vivo recordings during exploration or navigation.

Sharp wave ripples

Fast oscillations that underlie memory transfer across brain regions during consolidation.

In situ hybridization

(ISH). A histological approach that enables RNA to be labelled in tissue sections.

Next-generation RNA sequencing

A technique that measures whole-genome RNA abundance in a sample via reverse transcription, amplification and sequencing.

About this article

Publication history

Published

Issue Date

DOI

https://doi.org/10.1038/s41583-019-0125-5