Brain Structure and Function

, Volume 220, Issue 5, pp 2873–2893 | Cite as

Identification of dorsal–ventral hippocampal differentiation in neonatal rats

  • Kally C. O’Reilly
  • Arnar Flatberg
  • Sobia Islam
  • Lene C. Olsen
  • Ingvild Ulsaker Kruge
  • Menno P. Witter
Original Article


The adult hippocampal formation (HF) is functionally, connectionally, and transcriptionally differentiated along the dorsal–ventral axis. At birth, the hippocampus appears shortened along its dorsal–ventral axis. We therefore questioned at what postnatal age the differentiated dorsal–ventral hippocampus is present. We first established that the ventral tissue in the short postnatal hippocampus remains ventral in the adult-like hippocampus. Second, using anatomical tracing techniques we report that, within the first postnatal week, the main input from the entorhinal cortex (EC) to HF is topographically organized. The terminal distribution of this input along the dorsal–ventral axis of HF was related to a dorsolateral-to-ventromedial axis of origin in EC, thus reflecting adult topography. Finally, we examined gene expression along the dorsal–ventral axis in the developing hippocampus. We found that several genes that were differentially enriched in the adult dorsal and ventral hippocampus were similarly enriched in the dorsal and ventral hippocampal poles at birth. The differentially expressed genes relate to different molecular pathways and biomarkers of disease. Taken together, these data lead us to conclude that the entire dorsal–ventral axis of HF is present at birth showing adult-like functional differentiation. Moreover, our findings indicate that the neonatal ventral hippocampus is enriched with biomarkers associated with mental illnesses. These include schizophrenia, affective and anxiety disorders, disorders previously deemed as ventral hippocampal associated disorders, as well as alcoholism. Our results thus suggest an early developmental susceptibility of the ventral HF to mental illness.


Development Dorsal–ventral hippocampus Hippocampal transcription Entorhinal–hippocampal connectivity 



This work was supported by the Kavli Foundation, an EU 7th framework grant (‘Spacebrain’ grant # 200873), and Centre of Excellence (# 145993), equipment (# 181676), and research (#191929) grants from the Norwegian Research Council. The authors would like to thank Bruno Monterotti for technical help and Paulo Girão for help with MatLab.

Conflict of interest

The authors declare no conflict of interest.


  1. Abdulla FA, Bradbury E, Calaminici MR, Lippiello PM, Wonnacott S, Gray JA, Sinden JD (1996) Relationship between up-regulation of nicotine binding sites in rat brain and delayed cognitive enhancement observed after chronic or acute nicotinic receptor stimulation. Psychopharmacology 124(4):323–331CrossRefPubMedGoogle Scholar
  2. Alberi L, Liu S, Wang Y, Badie R, Smith-Hicks C, Wu J, Pierfelice TJ, Abazyan B, Mattson MP, Kuhl D, Pletnikov M, Worley PF, Gaiano N (2011) Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 69(3):437–444. doi: 10.1016/j.neuron.2011.01.004
  3. Andersen CL, Jensen JL, Orntoft TF (2004) Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 64(15):5245–5250. doi: 10.1158/0008-5472.CAN-04-0496 CrossRefPubMedGoogle Scholar
  4. Ansorge MS, Hen R, Gingrich JA (2007) Neurodevelopmental origins of depressive disorders. Curr Opin Pharmacol 7(1):8–17. doi: 10.1016/j.coph.2006.11.006 CrossRefPubMedGoogle Scholar
  5. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29. doi: 10.1038/75556 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Bachevalier J, Beauregard M (1993) Maturation of medial temporal lobe memory functions in rodents, monkeys, and humans. Hippocampus 3 Spec No:191–201Google Scholar
  7. Bannerman DM, Yee BK, Good MA, Heupel MJ, Iversen SD, Rawlins JN (1999) Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions. Behav Neurosci 113(6):1170–1188CrossRefPubMedGoogle Scholar
  8. Bannerman DM, Grubb M, Deacon RM, Yee BK, Feldon J, Rawlins JN (2003) Ventral hippocampal lesions affect anxiety but not spatial learning. Behav Brain Res 139(1–2):197–213CrossRefPubMedGoogle Scholar
  9. Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, Zhang WN, Pothuizen HH, Feldon J (2004) Regional dissociations within the hippocampus—memory and anxiety. Neurosci Biobehav Rev 28(3):273–283. doi: 10.1016/j.neubiorev.2004.03.004 CrossRefPubMedGoogle Scholar
  10. Bayer SA (1980) Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography. J Comp Neurol 190(1):87–114. doi: 10.1002/cne.901900107 CrossRefPubMedGoogle Scholar
  11. Brooks JM, Sarter M, Bruno JP (2011) Transient inactivation of the neonatal ventral hippocampus permanently disrupts the mesolimbic regulation of prefrontal cholinergic transmission: implications for schizophrenia. Neuropsychopharmacology 36(12):2477–2487. doi: 10.1038/npp.2011.136 PubMedCentralCrossRefPubMedGoogle Scholar
  12. Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM (2011) A critical role for IGF-II in memory consolidation and enhancement. Nature 469(7331):491–497. doi: 10.1038/nature09667 PubMedCentralCrossRefPubMedGoogle Scholar
  13. Christensen T, Bisgaard CF, Nielsen HB, Wiborg O (2010) Transcriptome differentiation along the dorso-ventral axis in laser-captured microdissected rat hippocampal granular cell layer. Neuroscience 170(3):731–741. doi: 10.1016/j.neuroscience.2010.07.016 CrossRefPubMedGoogle Scholar
  14. Costa RM, Honjo T, Silva AJ (2003) Learning and memory deficits in Notch mutant mice. Curr Biol 13(15):1348–1354CrossRefPubMedGoogle Scholar
  15. Czerniawski J, Yoon T, Otto T (2009) Dissociating space and trace in dorsal and ventral hippocampus. Hippocampus 19(1):20–32. doi: 10.1002/hipo.20469 CrossRefPubMedGoogle Scholar
  16. Deng JB, Yu DM, Wu P, Li MS (2007) The tracing study of developing entorhino-hippocampal pathway. Int J Dev Neurosci 25(4):251–258. doi: 10.1016/j.ijdevneu.2007.03.002 CrossRefPubMedGoogle Scholar
  17. Dolorfo CL, Amaral DG (1998) 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(1):25–48. doi: 10.1002/(SICI)1096-9861 CrossRefPubMedGoogle Scholar
  18. Dong HW, Swanson LW, Chen L, Fanselow MS, Toga AW (2009) Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc Natl Acad Sci USA 106(28):11794–11799. doi: 10.1073/pnas.0812608106 PubMedCentralCrossRefPubMedGoogle Scholar
  19. Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65(1):7–19. doi: 10.1016/j.neuron.2009.11.031 PubMedCentralCrossRefPubMedGoogle Scholar
  20. Forster E, Zhao S, Frotscher M (2006) Laminating the hippocampus. Nat Rev Neurosci 7(4):259–267. doi: 10.1038/nrn1882 CrossRefPubMedGoogle Scholar
  21. Freedman R, Goldowitz D (2010) Studies on the hippocampal formation: from basic development to clinical applications: studies on schizophrenia. Prog Neurobiol 90(2):263–275. doi: 10.1016/j.pneurobio.2009.10.008 PubMedCentralCrossRefPubMedGoogle Scholar
  22. Insausti R, Amaral DG (2004) Hippocampal formation. In: Paxinos G, Mai JK (eds) The human nervous system. Elsevier Academic Press, San Diego, pp 872–915Google Scholar
  23. Jacobson S (1963) Sequence of myelinization in the brain of the albino rat. A. Cerebral cortex, thalamus and related structures. J Comp Neurol 121:5–29CrossRefPubMedGoogle Scholar
  24. Jinno S, Kosaka T (2006) Cellular architecture of the mouse hippocampus: a quantitative aspect of chemically defined GABAergic neurons with stereology. Neurosci Res 56(3):229–245. doi: 10.1016/j.neures.2006.07.007 CrossRefPubMedGoogle Scholar
  25. Jinno S, Kosaka T (2010) Stereological estimation of numerical densities of glutamatergic principal neurons in the mouse hippocampus. Hippocampus 20(7):829–840. doi: 10.1002/hipo.20685 PubMedGoogle Scholar
  26. Kenney JW, Raybuck JD, Gould TJ (2012) Nicotinic receptors in the dorsal and ventral hippocampus differentially modulate contextual fear conditioning. Hippocampus 22(8):1681–1690. doi: 10.1002/hipo.22003 PubMedCentralCrossRefPubMedGoogle Scholar
  27. Kjelstrup KB, Solstad T, Brun VH, Hafting T, Leutgeb S, Witter MP, Moser EI, Moser MB (2008) Finite scale of spatial representation in the hippocampus. Science 321(5885):140–143. doi: 10.1126/science.1157086 CrossRefPubMedGoogle Scholar
  28. Lagali PS, Corcoran CP, Picketts DJ (2010) Hippocampus development and function: role of epigenetic factors and implications for cognitive disease. Clin Genet 78(4):321–333. doi: 10.1111/j.1399-0004.2010.01503.x CrossRefPubMedGoogle Scholar
  29. Law AJ, Pei Q, Walker M, Gordon-Andrews H, Weickert CS, Feldon J, Pryce CR, Harrison PJ (2009) Early parental deprivation in the marmoset monkey produces long-term changes in hippocampal expression of genes involved in synaptic plasticity and implicated in mood disorder. Neuropsychopharmacology 34(6):1381–1394. doi: 10.1038/npp.2008.106 PubMedCentralCrossRefPubMedGoogle Scholar
  30. Leonardo ED, Richardson-Jones JW, Sibille E, Kottman A, Hen R (2006) Molecular heterogeneity along the dorsal–ventral axis of the murine hippocampal CA1 field: a microarray analysis of gene expression. Neuroscience 137(1):177–186. doi: 10.1016/j.neuroscience.2005.08.082 CrossRefPubMedGoogle Scholar
  31. Lillrank SM, Lipska BK, Weinberger DR (1995) Neurodevelopmental animal models of schizophrenia. Clin Neurosci 3(2):98–104PubMedGoogle Scholar
  32. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. doi: 10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  33. Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat Rev Neurosci 7(2):93–102. doi: 10.1038/nrn1847 CrossRefPubMedGoogle Scholar
  34. Meier S, Brauer AU, Heimrich B, Nitsch R, Savaskan NE (2004) Myelination in the hippocampus during development and following lesion. Cell Mol Life Sci 61(9):1082–1094. doi: 10.1007/s00018-004-3469-5 CrossRefPubMedGoogle Scholar
  35. Meyer F, Peterschmitt Y, Louilot A (2009) Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats. Eur J Neurosci 29(10):2035–2048. doi: 10.1111/j.1460-9568.2009.06755.x CrossRefPubMedGoogle Scholar
  36. Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8(6):608–619. doi: 10.1002/(SICI)1098-1063 CrossRefPubMedGoogle Scholar
  37. Moser E, Moser MB, Andersen P (1993) Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J Neurosci 13(9):3916–3925PubMedGoogle Scholar
  38. Moser MB, Moser EI, Forrest E, Andersen P, Morris RG (1995) Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci USA 92(21):9697–9701PubMedCentralCrossRefPubMedGoogle Scholar
  39. Narr KL, Thompson PM, Szeszko P, Robinson D, Jang S, Woods RP, Kim S, Hayashi KM, Asunction D, Toga AW, Bilder RM (2004) Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 21(4):1563–1575. doi: 10.1016/j.neuroimage.2003.11.011 CrossRefPubMedGoogle Scholar
  40. O’Reilly KC, Gulden Dahl A, Ulsaker Kruge I, Witter MP (2013) Subicular–parahippocampal projections revisited: development of a complex topography in the rat. J Comp Neurol 521(18):4284–4299. doi: 10.1002/cne.23417
  41. Patel J, Fujisawa S, Berenyi A, Royer S, Buzsaki G (2012) Traveling theta waves along the entire septotemporal axis of the hippocampus. Neuron 75(3):410–417. doi: 10.1016/j.neuron.2012.07.015 PubMedCentralCrossRefPubMedGoogle Scholar
  42. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier Inc., LondonGoogle Scholar
  43. Pokorny J, Yamamoto T (1981) Postnatal ontogenesis of hippocampal CA1 area in rats. I. Development of dendritic arborisation in pyramidal neurons. Brain Res Bull 7(2):113–120CrossRefPubMedGoogle Scholar
  44. Posener JA, Wang L, Price JL, Gado MH, Province MA, Miller MI, Babb CM, Csernansky JG (2003) High-dimensional mapping of the hippocampus in depression. Am J Psychiatry 160(1):83–89CrossRefPubMedGoogle Scholar
  45. Royer S, Sirota A, Patel J, Buzsaki G (2010) Distinct representations and theta dynamics in dorsal and ventral hippocampus. J Neurosci 30(5):1777–1787. doi: 10.1523/JNEUROSCI.4681-09.2010 PubMedCentralCrossRefPubMedGoogle Scholar
  46. Rudy JW, Morledge P (1994) Ontogeny of contextual fear conditioning in rats: implications for consolidation, infantile amnesia, and hippocampal system function. Behav Neurosci 108(2):227–234CrossRefPubMedGoogle Scholar
  47. Sansom SN, Livesey FJ (2009) Gradients in the brain: the control of the development of form and function in the cerebral cortex. Cold Spring Harb Perspect Biol 1(2):a002519. doi: 10.1101/cshperspect.a002519 PubMedCentralCrossRefPubMedGoogle Scholar
  48. Schenk F (1985) Development of place navigation in rats from weaning to puberty. Behav Neural Biol 43(1):69–85CrossRefPubMedGoogle Scholar
  49. Schlessinger AR, Cowan WM, Swanson LW (1978) The time of origin of neurons in Ammon’s horn and the associated retrohippocampal fields. Anat Embryol (Berl) 154(2):153–173CrossRefGoogle Scholar
  50. Segal M, Richter-Levin G, Maggio N (2010) Stress-induced dynamic routing of hippocampal connectivity: a hypothesis. Hippocampus 20(12):1332–1338. doi: 10.1002/hipo.20751 CrossRefPubMedGoogle Scholar
  51. Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011) A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci 12(10):585–601. doi: 10.1038/nrn3085 PubMedCentralCrossRefPubMedGoogle Scholar
  52. Smith GN, Lang DJ, Kopala LC, Lapointe JS, Falkai P, Honer WG (2003) Developmental abnormalities of the hippocampus in first-episode schizophrenia. Biol Psychiatry 53(7):555–561CrossRefPubMedGoogle Scholar
  53. Smyth GK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:Article3. doi: 10.2202/1544-6115.1027
  54. Steffenach HA, Witter MP, Moser MB, Moser EI (2005) Spatial memory in the rat requires the dorsolateral band of the entorhinal cortex. Neuron 45(2):301–313CrossRefPubMedGoogle Scholar
  55. Tamamaki N (1999) Development of afferent fiber lamination in the infrapyramidal blade of the rat dentate gyrus. J Comp Neurol 411(2):257–266. doi: 10.1002/(SICI)1096-9861 CrossRefPubMedGoogle Scholar
  56. Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A, Puchalski RB, Gage FH, Jones AR, Bajic VB, Hawrylycz MJ, Lein ES (2008) Genomic anatomy of the hippocampus. Neuron 60(6):1010–1021. doi: 10.1016/j.neuron.2008.12.008 CrossRefPubMedGoogle Scholar
  57. Tseng KY, Chambers RA, Lipska BK (2009) The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res 204(2):295–305. doi: 10.1016/j.bbr.2008.11.039 PubMedCentralCrossRefPubMedGoogle Scholar
  58. van Groen T, Miettinen P, Kadish I (2003) The entorhinal cortex of the mouse: organization of the projection to the hippocampal formation. Hippocampus 13(1):133–149. doi: 10.1002/hipo.10037 CrossRefPubMedGoogle Scholar
  59. van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nat Rev Neurosci 10(4):272–282. doi: 10.1038/nrn2614 CrossRefPubMedGoogle Scholar
  60. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034Google Scholar
  61. Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, Furukawa K (2004) Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci USA 101(25):9458–9462. doi: 10.1073/pnas.0308126101 PubMedCentralCrossRefPubMedGoogle Scholar
  62. Witter MP (1989) Connectivity of the rat hippocampus. In: Chan-Palay V, Köhler C (eds) The Hippocampus—new vistas, neurology and neurobiology, vol 52. Alan R. Liss Inc., New York, pp 53–69Google Scholar
  63. Witter MP (2007a) Intrinsic and extrinsic wiring of CA3: indications for connectional heterogeneity. Learn Mem 14(11):705–713. doi: 10.1101/lm.725207 CrossRefPubMedGoogle Scholar
  64. Witter MP (2007b) The perforant path: projections from the entorhinal cortex to the dentate gyrus. Prog Brain Res 163:43–61. doi: 10.1016/S0079-6123(07)63003-9 CrossRefPubMedGoogle Scholar
  65. Witter MP, Amaral DG (2004) The hippocampal region. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier Academic Press, San Diego, pp 637–703Google Scholar
  66. Witter MP, Groenewegen HJ (1984) Laminar origin and septotemporal distribution of entorhinal and perirhinal projections to the hippocampus in the cat. J Comp Neurol 224(3):371–385. doi: 10.1002/cne.902240305 CrossRefPubMedGoogle Scholar
  67. Witter MP, Van Hoesen GW, Amaral DG (1989) Topographical organization of the entorhinal projection to the dentate gyrus of the monkey. J Neurosci 9(1):216–228PubMedGoogle Scholar
  68. Witter MP, Naber PA, van Haeften T, Machielsen WC, Rombouts SA, Barkhof F, Scheltens P, Lopes da Silva FH (2000a) Cortico-hippocampal communication by way of parallel parahippocampal-subicular pathways. Hippocampus 10(4):398–410. doi: 10.1002/1098-1063
  69. Witter MP, Wouterlood FG, Naber PA, Van Haeften T (2000b) Anatomical organization of the parahippocampal–hippocampal network. Ann N Y Acad Sci 911:1–24CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kally C. O’Reilly
    • 1
    • 3
  • Arnar Flatberg
    • 2
  • Sobia Islam
    • 1
  • Lene C. Olsen
    • 2
  • Ingvild Ulsaker Kruge
    • 1
  • Menno P. Witter
    • 1
  1. 1.Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Medical Technical Research CentreNorwegian University of Science and TechnologyTrondheimNorway
  2. 2.Institute for Cancer Research and Molecular MedicineNTNUTrondheimNorway
  3. 3.Center for Neural ScienceNew York UniversityNew YorkUSA

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