Cited by 1,153Point processes and geometric inequalitiesMemory and Neural MechanismsClassical Anatomy and Histology

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Unbiased stereological estimation of the number of neurons in the human hippocampus

West, Mark J., Gundersen, H. J. G.·1990·Journal of Comparative Neurology

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Abstract

The total numbers of neurons in five subdivisions of human hippocampi were estimated using unbiased Stereological principles and systematic sampling techniques. The method addresses the problems associated with the results and conclusions of previous quantitative studies, virtually all of which have been based on biased estimates of neuron densities. For each subdivision, the total number of neurons was calculated as the product of the estimate of the volume of the neuron‐containing layers and the estimate of the numerical density of neurons in the layers. Each hippocampus was cut into 3‐mm‐thick slabs, transverse to the rostrocaudal axis. One 70‐μUm‐thick section from each slab was used in the analysis. The volumes of the layers containing neurons in five major subdivisions of the hippocampus (granule cell layer, hilus, CA3–2, CA1, and subiculum) were estimated with point‐counting techniques after delineation of the layers on each section. The numerical densities of neurons in each subdivision were estimated on the same sections with optical directors. The sampling used in both estimates was performed systematically in all three dimensions. In an example of five hippocampi, the mean numbers of neurons (CV = SD/mean) in the different subdivisions were as follows: granule cells 15 × 10 6 (0.28), hilus 2.0 × 10 6 (0.16), CA3‐2 2.7 × 10 6 (0.22), CA1 16 × 10 6 (0.32), subiculum 4.5 × 10 6 (0.19). The stereological measurements contributed approximately 25% of the observed variance. Among the five subjects there was a significant inverse relationship between age (which ranged from 47 to 85 years) and the total number of neurons in CA1 (which ranged from 24 to 11 × 10 6). An optimized sampling scheme for studies of the number of neurons in the human hippocampus has been designed on the basis of an analysis of variance of the estimates at different levels of the sampling scheme. Counting neurons in the five subdivisions of the human hippocampus with the optimized sampling scheme takes less than 4 hours.

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Background
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Method
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Background
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Background
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“(West and Gundersen, 1990; West, 1999).”
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Background
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“Hans Jørgen Gundersen (Stereological Research Laboratory, Aarhus University), is sincerely thanked for help with the stereological design.”
Method
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Method
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“The most reliable way to estimate neuron numbers is stereologic sampling with fractionator and optical dissector (Gundersen et al., 1988; West & Gundersen, 1990; West, 1999).”
BackgroundMethod
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“The precision of all estimates was described with the Matheron transitive coefficient of error method, as described previously (West and Gundersen, 1990).”
Method
Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons
Little, C. M., Coons, K. D., & Sengelaub, D. R. (2008) · The Journal of Comparative Neurology · doi:10.1002/cne.21885 · Cited by 40
Calretinin-immunoreactive local circuit neurons in area 17 of the cynomolgus monkey,Macaca fascicularis
Meskenaïte, V. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970303)379:1 · Cited by 180
The use of the optical disector to estimate the number of neurons, glial and endothelial cells in the spinal cord of the mouse — with a comparative note on the rat spinal cord
Bjugn, R. (1993) · Brain Research · doi:10.1016/0006-8993(93)90744-8 · Cited by 40
How to count
West, M. J., & Coleman, P. D. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00061-9 · Cited by 40
Self-citation
Judgment of Emotional Nonlinguistic Vocalizations: Age-Related Differences
Fecteau, S., Armony, J. L., Joanette, Y., & Belin, P. (2005) · Applied Neuropsychology · doi:10.1207/s15324826an1201_7 · Cited by 45
“…Jack et al., 1997; Jernigan et al., 1991), postmortem (Davis, Schmitt, Wekstein, & Markesbery, 1999) and neurobiology studies (West, 1993a, 1993b; West & Gundersen, 1990; for reviews, see Adams & Jones, 1987; Coleman & Flood, 1987; Curcio, Buell, & Coleman, 1982; Detoledo–Morrell, Geinisman, &…”
Neurite growth from, and neuronal survival within, cultured explants of the nervous system: A critical review of morphometric and stereological methods, and suggestions for the future
Oorschot, D. E., Peterson, D. A., & Jones, D. G. (1991) · Progress in Neurobiology · doi:10.1016/0301-0082(91)90007-n · Cited by 37
IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP
Nadjar, A., Berton, O., Guo, S., Leneuve, P., Doveró, S., Diguet, E., Tison, F., Zhao, B., Holzenberger, M., & Bézard, E. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.02.009 · Cited by 41
Cytoarchitecture, areas, and neuron numbers of the Etruscan Shrew cortex
Naumann, R. K., Anjum, F., Roth-Alpermann, C., & Brecht, M. (2012) · The Journal of Comparative Neurology · doi:10.1002/cne.23053 · Cited by 39
“Optical disectors are randomly placed on a series of sections and used to count the number of particles (nucleoli) that come into focus and fall within the acceptance lines of the disector (Howard and Reed, 2005; West and Gundersen, 1990; West et al., 1991).”
Method
Astrocyte proliferation in the chick auditory brainstem following cochlea removal
Lurie, D. I., & Rubel, E. W. (1994) · The Journal of Comparative Neurology · doi:10.1002/cne.903460207 · Cited by 39
Monocular deprivation alters the morphology of glial fibrillary acidic protein-immunoreactive astrocytes in the rat visual cortex
Hawrylak, N., & Greenough, W. T. (1995) · Brain Research · doi:10.1016/0006-8993(95)00374-y · Cited by 39
Chronic Treatment with the 5-HT1A Receptor Partial Agonist Tandospirone Increases Hippocampal Neurogenesis
Mori, M., Murata, Y., Matsuo, A., Takemoto, T., & Mine, K. (2014) · Neurology and Therapy · doi:10.1007/s40120-013-0015-0 · Cited by 38
Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells
Sun, T., Shi, Q., Zhang, Y., Power, C., Hoesch, C., Antonelli, S., Schroeder, M. K., Caldarone, B. J., Taudte, N., Schenk, M., et al. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.06.037 · Cited by 41
Neuroprotective Potential of Adenosine A2Aand Cannabinoid CB1Receptor Antagonists in an Animal Model of Parkinson Disease
Cerri, S., Levandis, G., Ambrosi, G., Montepeloso, E., Antoninetti, G., Franco, R., Lanciego, J. L., Baqi, Y., Müller, C. E., Pinna, A., et al. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000064 · Cited by 38
Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology
Sadowski, M. J., Wı́sniewski, H. M., Tarnawski, M. J., Kozlowski, P. B., Lach, B., & Węgiel, J. (1999) · Acta Neuropathologica · doi:10.1007/s004010050968 · Cited by 38
“The coefficient of error, as a measure of the sampling accuracy [25, 69 ], was calculated for each case and each layer separately, and it was found to be less than 0.06.”
Influential
The Decrease of Pineal Melatonin Production with Age
Humbert, W., & Pévet, P. (1994) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1994.tb56819.x · Cited by 38
Effects of mild protein prenatal malnutrition and subsequent postnatal nutritional rehabilitation on noradrenaline release and neuronal density in the rat occipital cortex
Soto‐Moyano, R., Fernandez, V., Sanhueza, M., Belmar, J., Kusch, C., Pérez, H., Ruíz, S., & Hernández, A. (1999) · Developmental Brain Research · doi:10.1016/s0165-3806(99)00074-7 · Cited by 38
A quantitative analysis of parvalbumin neurons in rabbit auditory neocortex
McMullen, N. T., Smelser, C. B., & de Venecia, R. K. (1994) · The Journal of Comparative Neurology · doi:10.1002/cne.903490402 · Cited by 38
Duration of neurofibrillary changes in the hippocampal pyramidal neurons
Bobinski, M., Węgiel, J., Tarnawski, M. J., Bobinski, M., de Leon, M. J., Reisberg, ‌., Miller, D. C., & Wı́sniewski, H. M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00441-7 · Cited by 38
Identification of an Amino Acid Sequence Motif in the Cytoplasmic Domain of the NCAM‐140 kDa Isoform Essential for Its Neuritogenic Activity
Kolkova, K., Pedersen, N. M., Berezin, V., & Bock, E. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.751274.x · Cited by 38
“…neurite length in micrometers per cell can subsequently be calculated from the ratio of the number of cell processes intersecting the test lines and the number of cell bodies within the counting frame (for details, see West and Gundersen, 1990; Ventimiglia et al., 1995, Geinisman et al., 1996).”
Background
Interindividual differences of medial temporal lobe activation during encoding in an elderly population studied by fMRI
Vandenbroucke, M. W. G., Goekoop, R., Duschek, E. J. J., Netelenbos, J. C., Kuijer, J. P. A., Barkhof, F., Scheltens, P., & Rombouts, S. A. R. B. (2003) · NeuroImage · doi:10.1016/j.neuroimage.2003.09.043 · Cited by 38
Comparative analyses of the neuron numbers and volumes of the amygdaloid complex in old and new world primates
Carlo, C. N., Stefanacci, L., Semendeferi, K., & Stevens, C. F. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22264 · Cited by 38
Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease
Zhao, Q. S., Cai, D., & Bai, Y. (2013) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2013.1450 · Cited by 37
“The optical density (OD) of the striatal dopaminergic fibers was analyzed using Image-Pro Plus Software (Media Cybernetics, Inc., Rockville, MD, USA), according to a previously described optical dissector method (26,27).”
Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration
Jiménez-Ferrer, I., Jewett, M. A. S., Tontanahal, A., Romero‐Ramos, M., & Swanberg, M. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.07.016 · Cited by 37
“Unbiased stereological estimations of the total number of TH+ cells in the SNwere performed according to the optical fractionator principle (West and Gundersen, 1990) as described previously (Kurowska et al., 2016).”
Levels of glial cell line‐derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson’s disease
Virachit, S., Mathews, K. J., Cottam, V., Werry, E. L., Galli, E., Rappou, E., Lindholm, P., Saarma, M., Halliday, G. M., Weickert, C. S., et al. (2019) · Brain Pathology · doi:10.1111/bpa.12730 · Cited by 37
“These data are consistent with previous quantitative measures of cell density in normal aging (27, 73, 89), as well as with reports of hippocampal atrophy (7) without neuronal loss in PD (27, 37).”
Result
Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats
Kıray, M., Bagriyanik, H., Pekçetin, Ç., Ergür, B. U., Uysal, N., Özyurt, D., & Buldan, Z. (2006) · Physiological Research · doi:10.33549/physiolres.930742 · Cited by 37
Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia–ischemia
Cameron, S. H., Alwakeel, A. J., Goddard, L., Hobbs, C. E., Gowing, E. K., Barnett, E. R., Kohe, S. E., Sizemore, R. J., & Oorschot, D. E. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.03.019 · Cited by 36
“This generally complied with or exceeded the guideline of sampling 1–2 cells per disector volume (West and Gundersen, 1990).”
Influential
Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats
Steece‐Collier, K., Soderstrom, K. E., Collier, T. J., Sortwell, C. E., & Lad, E. M. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22037 · Cited by 36
Cortical thickness, neuron density and size in the inferior parietal lobe in schizophrenia
Smiley, J. F., Konnova, K., & Bleiwas, C. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.01.006 · Cited by 35
“, 2007), and it is estimated that less than 10% of this variance is due to measurement imprecision (West and Gundersen, 1990).”
Background
Hippocampal granule cell loss in human chronic alcohol abusers
Dhanabalan, G., Maître, T. W. L., Bogdanović, N., Alkass, K., & Druid, H. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.08.011 · Cited by 42
Connectomics of the Octopus vulgaris vertical lobe provides insight into conserved and novel principles of a memory acquisition network
Bidel, F., Meirovitch, Y., Schalek, R. L., Lu, X., Pavarino, E. C., Yang, F., Peleg, A., Wu, Y., Shomrat, T., Berger, D. R., et al. (2023) · eLife · doi:10.7554/elife.84257 · Cited by 36
A role for mixed lineage kinases in granule cell apoptosis induced by cytoskeletal disruption
Müller, G. J., Geist, M. A., Veng, L., Willesen, M. G., Johansen, F. F., Leist, M., & Vaudano, E. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03590.x · Cited by 36
“The unbiased optical fractionator method (West and Gundersen 1990; West et al. 1991) was used for sampling and estimation of numbers of positive profiles per unit area ipsilateral to the side of colchicine injection.”
Method
Effect of the mitochondrial antioxidant, Mito Vitamin E, on hypoxic–ischemic striatal injury in neonatal rats: A dose–response and stereological study
Covey, M. V., Murphy, M. P., Hobbs, C., Smith, R. A. J., & Oorschot, D. E. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2005.12.026 · Cited by 36
Chronic cerebrovascular ischemia in aged rats: effects on brain metabolic capacity and behavior☆
Cada, A. M., de la Torre, J. C., & Gonzalez-Lima, F. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00116-0 · Cited by 36
Dendritic regression dissociated from neuronal death but associated with partial deafferentation in aging rat supraoptic nucleus
Flood, D. G., & Coleman, P. D. (1993) · Neurobiology of Aging · doi:10.1016/0197-4580(93)90042-a · Cited by 36
TrkB but not trkC receptors are necessary for postnatal maintenance of hippocampal spines
von Bohlen und Halbach, O., Minichiello, L., & Unsicker, K. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.028 · Cited by 37
Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome
Węgiel, J., Flory, M. J., Kuchna, I., Nowicki, K., Wegiel, J., Ma, S. Y., Zhong, N., Wierzba‐Bobrowicz, T., de Leon, M., Lai, F., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01300-9 · Cited by 35
“Leak of fibrillar amyloid at the core periphery results in exposure of surrounding dendrites, axons, and synapses to direct contact with amyloid, leading to degeneration of mitochondria and cytoskeleton and accumulation in swelling segments of neuronal processes and synapses of residues of neuron organelles, cytoskele…”
Background
NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss
Španić, E., Horvat, L. L., Ilić, K., Hof, P. R., & Šimić, G. (2022) · Cells · doi:10.3390/cells11142223 · Cited by 35
“The second step was measuring the numerical density of neurons and NFTs by using the disector method [47].”
Method
Differential regulation of inhibitors of apoptosis proteins in Alzheimer’s disease brains
Christie, L., Su, J. H., Tu, C. H., Dick, M. B., Zhou, J., & Cotman, C. W. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.017 · Cited by 35
Patterns of colocalization of neuronal nitric oxide synthase and somatostatin-like immunoreactivity in the mouse hippocampus: quantitative analysis with optical disector
Jinno, S., & Kosaka, T. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.027 · Cited by 35
Impact of environmental enrichment on neurogenesis in the dentate gyrus during the early postnatal period
Rizzi, S., Bianchi, P., Guidi, S., Ciani, E., & Bartesaghi, R. (2011) · Brain Research · doi:10.1016/j.brainres.2011.08.007 · Cited by 35
Stress and Glucocorticoid Contributions to Normal and Pathological Aging
Goosens, K. A., & Sapolsky, R. M. (2007) · CRC Press eBooks · doi:10.1201/9781420005523-13 · Cited by 41
Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion
Sargin, D., Hassouna, I. A., Sperling, S., Sirén, A., & Ehrenreich, H. (2008) · Glia · doi:10.1002/glia.20797 · Cited by 36

Authors: West, M. J., & Gundersen, H. J. G.
Affiliations: Aarhus University (DK)
Corresponding author: West, Mark J.
ORCID: West, Mark J.
Venue: Journal of Comparative Neurology
Publisher: Wiley
Published: 1990-06
Volume: 296
Issue: 1
Pages: 1-22
ISSN: 0021-9967 (ISSN-L)
1096-9861
DOI: 10.1002/cne.902960102
OpenAlex: W2014892312
Cited by: 1,153
References: 47
Citations by year: 2026: 7 · 2025: 13 · 2024: 10 · 2023: 17 · 2022: 24 · 2021: 22 · 2020: 24 · 2019: 19 · 2018: 40 · 2017: 27 · 2016: 32 · 2015: 30 · 2014: 38 · 2013: 40 · 2012: 41
FWCI: 46.01
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 5244 d)
Locations: The Journal of Comparative Neurology (publishedVersion)
PubMed (publishedVersion)
Funders: Sundhed og Sygdom, Det Frie Forskningsråd
Topics: Physical Sciences › Mathematics › Applied Mathematics › Point processes and geometric inequalities
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Health Sciences › Medicine › Anatomy › Classical Anatomy and Histology
Keywords: human hippocampus, neuron number estimation, neuronal density, unbiased stereology, optical disector, point counts, CA1, CA3, subiculum, granular layer, hilus, age-related neuronal loss
MeSH terms: Aged, Aged, 80 and over, Cell Count, Hippocampus, Humans, Middle Aged

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Unbiased stereological estimation of the number of neurons in the human hippocampus

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