Quantification of neurons in the hippocampal formation of chimpanzees: comparison to rhesus monkeys and humans

A Correction to this article was published on 29 October 2020

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Abstract

The hippocampal formation is important for higher brain functions such as spatial navigation and the consolidation of memory, and it contributes to abilities thought to be uniquely human, yet little is known about how the human hippocampal formation compares to that of our closest living relatives, the chimpanzees. To gain insight into the comparative organization of the hippocampal formation in catarrhine primates, we quantified neurons stereologically in its major subdivisions—the granular layer of the dentate gyrus, CA4, CA2-3, CA1, and the subiculum—in archival brain tissue from six chimpanzees ranging from 29 to 43 years of age. We also sought evidence of Aβ deposition and hyperphosphorylated tau in the hippocampus and adjacent neocortex. A 42-year-old animal had moderate cerebral Aβ-amyloid angiopathy and tauopathy, but Aβ was absent and tauopathy was minimal in the others. Quantitatively, granule cells of the dentate gyrus were most numerous, followed by CA1, subiculum, CA4, and CA2-3. In the context of prior investigations of rhesus monkeys and humans, our findings indicate that, in the hippocampal formation as a whole, the proportions of neurons in CA1 and the subiculum progressively increase, and the proportion of dentate granule cells decreases, from rhesus monkeys to chimpanzees to humans. Because CA1 and the subiculum engender key hippocampal projection pathways to the neocortex, and because the neocortex varies in volume and anatomical organization among these species, these findings suggest that differences in the proportions of neurons in hippocampal subregions of catarrhine primates may be linked to neocortical evolution.

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Availability of data and material

Data are accessible in a public repository at https://github.com/anthrochristina/ChimpHippocampus.

Change history

  • 29 October 2020

    The original version of this article contained a mistake in Figs.��3 and 4.

References

  1. Amaral DG (1978) A Golgi study of cell types in the hilar region of the hippocampus in the rat. J Comp Neurol 182(5):851–914

    CAS  Google Scholar 

  2. Bartsch T, Döhring J, Rohr A, Jansen O, Deuschl G (2011) CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness. Proc Natl Acad Sci USA 108(42):17562–17567

    CAS  Google Scholar 

  3. Braak H, Braak EVA (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16(3):271–278

    CAS  Google Scholar 

  4. Carlesimo GA, Piras F, Orfei MD, Iorio M, Caltagirone C, Spalletta G (2015) Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer’s disease. Alzheimer’s Dement Diagn Assess Dis Monit 1(1):24–32

    Google Scholar 

  5. Clark RE, Squire LR (2013) Similarity in form and function of the hippocampus in rodents, monkeys, and humans. Proc Natl Acad Sci USA 110:10365–10370

    CAS  Google Scholar 

  6. Edler MK, Sherwood CC, Meindl RS, Hopkins WD, Ely JJ, Erwin JM, Raghanti MA (2017) Aged chimpanzees exhibit pathologic hallmarks of Alzheimer’s disease. Neurobiol Aging 59:107–120

    CAS  Google Scholar 

  7. Edler MK, Sherwood CC, Meindl RS, Munger EL, Hopkins WD, Ely JJ, Raghanti MA (2018) Microglia changes associated to Alzheimer’s disease pathology in aged chimpanzees. J Comp Neurol 526(18):2921–2936

    CAS  Google Scholar 

  8. Eichenbaum H (2017) Memory: organization and control. Annu Rev Psychol 68:19–45

    Google Scholar 

  9. Ekstrom AD, Kahana MJ, Caplan JB, Fields TA, Isham EA, Newman EL, Fried I (2003) Cellular networks underlying human spatial navigation. Nature 425(6954):184–188

    CAS  Google Scholar 

  10. Finch CE, Austad SN (2015) Commentary: is Alzheimer’s disease uniquely human? Neurobiol Aging 36(2):553–555

    Google Scholar 

  11. George S, Rönnbäck A, Gouras GK, Petit GH, Grueninger F, Winblad B, Brundin P (2014) Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun 2(1):17

    Google Scholar 

  12. Hartley T, Lever C, Burgess N, O’Keefe J (2014) Space in the brain: how the hippocampal formation supports spatial cognition. Philos Trans R Soc B Biol Sci 369(1635):20120510

    Google Scholar 

  13. Heuer E, Rosen RF, Cintron A, Walker LC (2012) Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr Pharm Des 18(8):1159–1169

    CAS  Google Scholar 

  14. Hoffman GE, Le WW (2004) Just cool it! Cryoprotectant anti-freeze in immunocytochemistry and in situ hybridization. Peptides 25(3):425–431

    CAS  Google Scholar 

  15. Insausti R (1993) Comparative anatomy of the entorhinal cortex and hippocampus in mammals. Hippocampus 3(S1):19–26

    Google Scholar 

  16. Jabès A, Lavenex PB, Amaral DG, Lavenex P (2011) Postnatal development of the hippocampal formation: a stereological study in macaque monkeys. J Comp Neurol 519(6):1051–1070

    Google Scholar 

  17. Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132

    CAS  Google Scholar 

  18. Jicha GA, Weaver C, Lane E, Vianna C, Kress Y, Rockwood J, Davies P (1999) cAMP-dependent protein kinase phosphorylations on tau in Alzheimer’s disease. J Neurosci 19(17):7486–7494

    CAS  Google Scholar 

  19. Keuker JI, Luiten PG, Fuchs E (2003) Preservation of hippocampal neuron numbers in aged rhesus monkeys. Neurobiol Aging 24(1):157–165

    Google Scholar 

  20. Kim KS, Miller DL, Sapienza VJ, Chen CMJ, Bai C, Grundke-Iqbal I, Wisniewski HM (1988) Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci Res Commun 2(3):121–130

    CAS  Google Scholar 

  21. Kitamoto T, Ogomori K, Tateishi J, Prusiner SB (1987) Formic acid pretreatment enhances immunostaining of cerebral and systemic amyloids. Lab Investig 57(2):230–236

    CAS  Google Scholar 

  22. Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 22(22):9785–9793

    CAS  Google Scholar 

  23. Lorente de Nó R (1933) Studies on the structure of the cerebral cortex. J Psychol Neurol 45:381–438

    Google Scholar 

  24. Manns JR, Eichenbaum H (2006) Evolution of declarative memory. Hippocampus 16(9):795–808

    Google Scholar 

  25. Mouton PR (2011) Unbiased stereology: a concise guide. The Johns Hopkins University Press, Baltimore

    Google Scholar 

  26. Munger EL, Edler MK, Hopkins WD, Ely JJ, Erwin JM, Perl DP, Raghanti MA (2019) Astrocytic changes with aging and Alzheimer’s disease-type pathology in chimpanzees. J Comp Neurol 527(7):1179–1195

    CAS  Google Scholar 

  27. Pittenger C, Huang YY, Paletzki RF, Bourtchouladze R, Scanlin H, Vronskaya S, Kandel ER (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34(3):447–462

    CAS  Google Scholar 

  28. Place R, Lykken C, Beer Z, Suh J, McHugh TJ, Tonegawa S, Sauvage MM (2012) NMDA signaling in CA1 mediates selectively the spatial component of episodic memory. Learn Mem 19(4):164–169

    CAS  Google Scholar 

  29. Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58(9):1395–1402

    CAS  Google Scholar 

  30. Rapoport SI (1990) Integrated phylogeny of the primate brain, with special reference to humans and their diseases. Brain Res Rev 15(3):267–294

    CAS  Google Scholar 

  31. Rapoport SI, Nelson PT (2011) Biomarkers and evolution in Alzheimer disease. Prog Neurobiol 95(4):510–513

    CAS  Google Scholar 

  32. Rasmussen T, Schliemann T, Sørensen JC, Zimmer J, West MJ (1996) Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging 17(1):143–147

    CAS  Google Scholar 

  33. Rosen RF, Farberg AS, Gearing M, Dooyema JM, Long P, Anderson DC, Duong TQ (2008) Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol 509(3):259–270

    Google Scholar 

  34. Rosen RF, Tomidokoro Y, Farberg AS, Dooyema J, Ciliax B, Preuss TM, Walker LC (2016) Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer’s disease. Neurobiol Aging 44:185–196

    CAS  Google Scholar 

  35. Rosene DL, Van Hoesen GW (1977) Hippocampal efferents reach widespread areas of cerebral cortex and amygdala in the rhesus monkey. Science 198(4314):315–317

    CAS  Google Scholar 

  36. Schacter DL, Addis DR, Szpunar KK (2017) Escaping the past: contributions of the hippocampus to future thinking and imagination. In: Hannula DE, Duff MC (eds) The hippocampus from cells to systems: structure, connectivity, and functional contributions to memory and flexible cognition. Springer, Cham, pp 439-465

    Google Scholar 

  37. Schmidt-Kastner R, Freund TF (1991) Selective vulnerability of the hippocampus in brain ischemia. Neuroscience 40(3):599–636

    CAS  Google Scholar 

  38. Schmitz C, Hof PR (2000) Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach. J Chem Neuroanat 20(1):93–114

    CAS  Google Scholar 

  39. Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130(4):813–831

    CAS  Google Scholar 

  40. Sherwood CC, Subiaul F, Zawidzki TW (2008) A natural history of the human mind: tracing evolutionary changes in brain and cognition. J Anat 212(4):426–454

    Google Scholar 

  41. Šimić G, Kostović I, Winblad B, Bogdanović N (1997) Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 379(4):482–494

    Google Scholar 

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

    CAS  Google Scholar 

  43. Stephan H, Manolescu J (1980) Comparative investigations on hippocampus in insectivores and primates. Z Mikrosk Anat Forsch 94(6):1025–1050

    CAS  Google Scholar 

  44. Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800

    Google Scholar 

  45. Todorov OS, Weisbecker V, Gilissen E, Zilles K, de Sousa AA (2019) Primate hippocampus size and organization are predicted by sociality but not diet. Proc R Soc B 286(1914):20191712

    Google Scholar 

  46. van Dijk RM, Huang SH, Slomianka L, Amrein I (2016) Taxonomic separation of hippocampal networks: principal cell populations and adult neurogenesis. Front Neuroanat 10:22

    Google Scholar 

  47. Van Essen DC, Donahue CJ, Glasser MF (2018) Development and evolution of cerebral and cerebellar cortex. Brain Behav Evol 91:158–169

    Google Scholar 

  48. Vanier DR, Sherwood CC, Smaers JB (2019) Distinct patterns of hippocampal and neocortical evolution in primates. Brain Behav Evol 93(4):171–181

    Google Scholar 

  49. Walker LC, Jucker M (2017) The exceptional vulnerability of humans to Alzheimer’s disease. Trends Mol Med 23(6):534–545

    Google Scholar 

  50. Waterson R, Lander E, Wilson R (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437:69–87

    Google Scholar 

  51. West MJ (1993) Regionally specific loss of neurons in the aging human hippocampus. Neurobiol Aging 14(4):287–293

    CAS  Google Scholar 

  52. West MJ, Gundersen HJG (1990) Unbiased stereological estimation of the number of neurons in the human hippocampus. J Comp Neurol 296(1):1–22

    CAS  Google Scholar 

  53. West MJ, Kawas CH, Martin LJ, Troncoso JC (2000) The CA1 region of the human hippocampus is a hot spot in Alzheimer’s disease. Ann N Y Acad Sci 908:255–259

    CAS  Google Scholar 

  54. Witter MP, Amaral DG (1995) Hippocampal formation. In: Paxinos G (ed) The Rat Nervous System. Academic Press, San Diego, pp 635–704

    Google Scholar 

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Acknowledgements

These data were in part collected while Rebecca Rosen was employed at Emory University (2004–2010). The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States Government.

Funding

This research was supported by National Institutes of Health (NIH) Grants P01 AG026423 (to James G. Herndon), P50 AG025688 (to Allan I. Levey), and P50 AG005138 (to Patrick R. Hof), and by the James S. McDonnell Foundation (JSMF 21002093) to Todd M. Preuss.

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CNRF, RFR, LCW, and TMP wrote the paper. RFR, LCW, TMP, PRH, and CCS designed the research. JMD and ASF prepared samples. CNRF, RFR, and ASF collected and analyzed data. PRH and CCS provided intellectual content and interpretation of results. All authors contributed to the final preparation of the manuscript and approved it for submission.

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Correspondence to Christina N. Rogers Flattery.

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Research was conducted on post-mortem/archival chimpanzee brain tissue that had been opportunistically collected at necropsy, thus IACUC approval was not required. All tissues were collected in accordance with federal and institutional guidelines for the humane care and use of experimental animals. The New Iberia and Yerkes Centers are fully accredited by AAALAC International.

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Rogers Flattery, C.N., Rosen, R.F., Farberg, A.S. et al. Quantification of neurons in the hippocampal formation of chimpanzees: comparison to rhesus monkeys and humans. Brain Struct Funct 225, 2521–2531 (2020). https://doi.org/10.1007/s00429-020-02139-x

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Keywords

  • Stereology
  • CA1 region
  • Dentate gyrus
  • Alzheimer’s disease
  • Abeta
  • Tauopathy