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Cited by 342Primate Behavior and EcologyNeurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology Research

Evolution of increased glia–neuron ratios in the human frontal cortex

Open access
Sherwood, Chet C., Stimpson, Cheryl D., Raghanti, Mary Ann, Wildman, Derek E., Uddin, Monica, Grossman, Lawrence I., Goodman, Morris, Redmond, John C. +3 more·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0605843103PMC PMC1564260
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Abstract

Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism. The current study examined whether there is a disproportionate increase in glial cell density in the human frontal cortex in comparison with other anthropoid primate species (New World monkeys, Old World monkeys, and hominoids) to support greater metabolic demands. Among 18 species of anthropoids, humans displayed the greatest departure from allometric scaling expectations for the density of glia relative to neurons in layer II/III of dorsolateral prefrontal cortex (area 9L). However, the human glia–neuron ratio in this prefrontal region did not differ significantly from allometric predictions based on brain size. Further analyses of glia–neuron ratios across frontal areas 4, 9L, 32, and 44 in a sample of humans, chimpanzees, and macaque monkeys showed that regions involved in specialized human cognitive functions, such as “theory of mind” (area 32) and language (area 44) have not evolved differentially higher requirements for metabolic support. Taken together, these findings suggest that greater metabolic consumption of human neocortical neurons relates to the energetic costs of maintaining expansive dendritic arbors and long-range projecting axons in the context of an enlarged brain.

AI snapshot

Written from the paper’s full text.

TL;DR

This comparative stereology study finds that humans have the highest glia–neuron ratio in dorsolateral prefrontal cortex among 18 anthropoid primates, but the human ratio is largely predicted by allometric scaling with brain size. The authors argue that increased glial support in human frontal cortex reflects metabolic costs of maintaining larger dendritic arbors and longer axons in an enlarged brain.

Key findings

  • In layer II/III of dorsolateral prefrontal area 9L, humans had the greatest departure from allometric expectations for glial density relative to neuron density: 46% more glia per neuron than expected from nonhuman species means and 32% more using independent contrasts.
  • Human area 9L glia–neuron ratio was 1.65, compared with 1.20 in chimpanzees, 1.21 in gorillas, 0.98 in orangutans, and 0.84 in *Macaca maura*.
  • Across frontal areas 4, 9L, 32, and 44 in humans, chimpanzees, and macaques, repeated-measures ANOVA found significant effects of species (*F*₂,₁₅ = 101.80, *P* < 0.001) and cortical area (*F*₃,₄₅ = 22.46, *P* < 0.001) but no species × area interaction (*F*₆,₄₅ = 1.19, *P* = 0.331).
  • Humans had significantly greater glia–neuron ratios than macaques in every cortical area examined and greater ratios than chimpanzees in area 4 and area 32, but not in area 9L (*P* = 0.104) or area 44 (*P* = 1.000).

Methods

  • Left-hemisphere postmortem brain samples from 18 anthropoid primate species were analyzed; interspecific allometric analyses used Nissl-stained layer II/III of dorsolateral prefrontal area 9L, and regional analyses compared humans, chimpanzees, and macaques (n = 6 each) in frontal areas 4, 9L, 32, and 44.
  • Neurons and glia were counted using the optical disector stereologic method; glia were not subdivided into astrocytes and oligodendrocytes, and microglia were excluded.
  • Allometric scaling used log-transformed species means, reduced major axis regression, phylogenetic independent contrasts, and least-squares prediction intervals; regional differences were tested with two-way repeated-measures ANOVA.

Limitations

  • The paper states that complete analyses of neuron and glial density scaling directly against brain weight were not performed because of possible artifacts related to tissue shrinkage of individual specimens.
  • The paper notes that many specimens came from different sources and fixation methods, including immersion fixation and transcardial perfusion in some nonhuman samples.
  • Evident from the text: sample sizes are small and uneven, with several species represented by only one or two individuals, and two juveniles were included; these factors limit confidence in species-level estimates and comparative inference.

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Integrity signals

Registry

Crossref · 10.1073/pnas.0605843103

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 69 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    In humans, glia-neuron ratios in area 4 differed significantly from all other frontal areas.

    “In humans, glia–neuron ratios in area 4 differed significantly from all other frontal areas (all comparisons, P < 0.05).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    Repeated-measures ANOVA revealed a significant main effect of species on glia-neuron ratios in layer II/III of areas 4, 9L, 32, and 44.

    “The ANOVA revealed a significant main effect of species (F2,15 = 101.80, P < 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Discussion

    Only a small proportion of the variance in glial density is explained by neuron density (r2 = 0.25, P = 0.035).

    “Although only a small proportion of the variance in glial density is explained by neuron density (r2 = 0.25, P = 0.035)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Using independent contrasts, human glial density fell within the 95% prediction intervals of the prediction for a hypothetical species attached to the branch leading to humans.

    “From this prediction, glial density in humans fell within the 95% PIs (observed log glial density = 5.19; predicted = 5.02; upper PI = 5.40, lower PI = 4.63)”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Bonferroni post hoc comparisons showed that areas 4 and 32 differed significantly in glia-neuron ratio from one another in macaques and chimpanzees.

    “Bonferroni post hoc comparisons showed that areas 4 and 32 differed significantly in glia–neuron ratio from one another in macaques and chimpanzees (all comparisons, P < 0.05).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data
    § Discussion

    Our analyses of species data and independent contrasts yielded similar allometric exponents; independent contrast slopes were always contained within the 95% CIs of slopes calculated from species data.

    “It is noteworthy that our analyses of species data and independent contrasts yielded similar allometric exponents: Independent contrast slopes were always contained within the 95% CIs of slopes calculated from species data.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    Axon diameter and length also increase in larger brains, contributing to the higher cost of neuronal activity.

    “Axon diameter and length also increase in larger brains (26), contributing to the higher cost of neuronal activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Harrison KH, Hof PR, Wang SS. J Neurocytol. 2002;31:289–298. doi: 10.1023/a:1024178127195. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    The metabolic rate per gram of neural tissue generally decreases with larger brain size, so the human brain is more energetically efficient than smaller-brained primate species.

    “At the same time, because the metabolic rate per gram of neural tissue generally decreases with larger brain size, the human brain is more energetically efficient than that in smaller-brained primate species (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Mink JW, Blumenschine RJ, Adams DB. Am J Physiol. 1981;241:R203–R212. doi: 10.1152/ajpregu.1981.241.3.R203. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Glia densities have been shown to increase along different segmental levels of Clarke's nucleus surrounding neurons that have progressively longer axon projections in the spinocerebellar tract.

    “In this context, it is interesting that glia densities have been shown to increase along different segmental levels of Clarke’s nucleus surrounding neurons that have progressively longer axon projections in the spinocerebellar tract (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Friede RL, Van Houten WH. Proc Natl Acad Sci USA. 1962;48:817–821. doi: 10.1073/pnas.48.5.817. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    Previous studies of glia-neuron ratios in the neocortex concluded that brain size is the main determinant of this variable across mammals.

    “Previous studies of glia–neuron ratios in the neocortex also concluded that brain size is the main determinant of this variable across mammals (22–24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Friede RL, Van Houten WH. Proc Natl Acad Sci USA. 1962;48:817–821. doi: 10.1073/pnas.48.5.817. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    The glia-neuron ratio increases with greater environmental enrichment and stimulation in rodents.

    “Several experimental studies in rodents, furthermore, have demonstrated that the glia–neuron ratio increases with greater environmental enrichment and stimulation (15, 16).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    The most distinctive cognitive capacities expressed by humans are the ability to use symbolic language in a recursive manner and to make inferences regarding the mental states of others (theory of mind).

    “Arguably, the most distinctive cognitive capacities expressed by humans are the ability to use symbolic language in a recursive manner (17) and to make inferences regarding the mental states of others, i.e., “theory of mind” (18).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Previous studies of glia-neuron ratios included relatively few species drawn from very diverse phylogenetic groups and represented a small number of cortical areas.

    “First, they included relatively few species drawn from very diverse phylogenetic groups, and they represented a small number of cortical areas.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Friede RL, Van Houten WH. Proc Natl Acad Sci USA. 1962;48:817–821. doi: 10.1073/pnas.48.5.817. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [23] Hawkins A, Olszewski J. Science. 1957;126:76–77. doi: 10.1126/science.126.3263.76. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [24] Tower DB, Young OM. J Neurochem. 1973;20:269–278. doi: 10.1111/j.1471-4159.1973.tb12126.x. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Abstract

    The tremendous growth of the human neocortex during postnatal development is due to elaboration of dendritic arbors and a 4-fold increase in glial cell numbers.

    “the tremendous growth of the neocortex during postnatal development is due to elaboration of dendritic arbors and a 4-fold increase in glial cell numbers (13, 14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

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    Interpretationown data
    § Discussion

    The scaling relationships observed in contemporary taxa represent changes that have occurred repeatedly throughout multiple nodes in the phylogenetic tree and represent robust functional regularities in neocortical design.

    “This finding indicates that the scaling relationships observed in contemporary taxa represent changes that have occurred repeatedly throughout multiple nodes in the phylogenetic tree and, hence, represent robust functional regularities in neocortical design.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Expansion of the human brain entails high metabolic costs.

    “Expansion of the human brain entails high metabolic costs (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning
    § Discussion

    Because previous scaling relationships were calculated based on contemporary species data, it was not clear whether these associations would be maintained after correcting for statistical nonindependence due to phylogenetic relatedness.

    “Second, because scaling relationships were calculated based on contemporary species data, it was not clear whether these associations would be maintained after correcting for statistical nonindependence due to phylogenetic relatedness.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Area 44 in the inferior frontal cortex is considered part of Broca's area for language production.

    “Area 44 in the inferior frontal cortex is considered part of Broca’s area for language production (19)”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    Neuronal activity level and energy expenditure per neuron have become enhanced in human evolution, even as mass-specific rates of brain metabolism declined.

    “Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism.”
    • Also stated in: § Abstract · hedged
      “Taken collectively, these findings suggest that neuronal activity level and energy expenditure per neuron have become enhanced in human evolution, even as mass-specific rates of brain metabolism declined.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Results

    The study did not perform complete analyses of neuron and glial density scaling directly against brain weight because of possible artifacts related to tissue shrinkage of individual specimens in this sample.

    “We did not perform complete analyses of neuron and glial density scaling directly against brain weight because of possible artifacts related to tissue shrinkage of individual specimens in this sample”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    The human brain comprises only approximately 2% of body mass but captures approximately 20% of the body's total glucose utilization.

    “Although the human brain comprises only ≈2% of body mass, it captures ≈20% of the body’s total glucose utilization (2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Sokoloff L. In: Handbook of Physiology, Section I, Neurophysiology. Field J, Magoun HW, Hall VE, editors. Vol 3. Washington, DC: Am Physiol Soc; 1960. pp. 1843–1864. [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Discussion

    The increased ratio of glia to neurons in the human frontal cortex might be explained by energy expenditures that are correlated with increasing neocortex size, which, in humans, accounts for 44% of the brain's total energy consumption.

    “The increased ratio of glia to neurons in the human frontal cortex might be explained by energy expenditures that are correlated with increasing neocortex size, which, in humans, accounts for 44% of the brain’s total energy consumption (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lennie P. Curr Biol. 2003;13:493–497. doi: 10.1016/s0960-9822(03)00135-0. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Each human neocortical neuron consumes 3.3 times more ATP to fire a single spike than in rats, and 2.6 times more energy to maintain resting potentials.

    “Considering the relatively greater surface area of neuronal soma, dendrites, and axons that accompany brain enlargement, it has been estimated that each human neocortical neuron consumes 3.3 times more ATP to fire a single spike than in rats, and 2.6 times more energy to maintain resting potentials (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lennie P. Curr Biol. 2003;13:493–497. doi: 10.1016/s0960-9822(03)00135-0. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Comparative studies of pyramidal neurons in granular prefrontal cortex have shown that human neurons display much larger dendritic arbors and more spines than those in primates with smaller brains (although hominoids have not yet been studied).

    “Comparative studies of pyramidal neurons in granular prefrontal cortex have shown that human neurons display much larger dendritic arbors and more spines than those in primates with smaller brains (although hominoids have not yet been studied) (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Elston GN, Benavides-Piccione R, Elston A, Zietsch B, DeFelipe J, Manger P, Casagrande V, Kaas JH. Anat Rec. 2006;288:A26–A35. doi: 10.1002/ar.a.20278. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    The two highest costs associated with neuronal activity come from excitatory postsynaptic potentials in the dendritic tree and propagation of action potentials along the axon.

    “The two highest costs associated with neuronal activity come from excitatory postsynaptic potentials in the dendritic tree and propagation of action potentials along the axon (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lennie P. Curr Biol. 2003;13:493–497. doi: 10.1016/s0960-9822(03)00135-0. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning
    § Conclusion

    The findings might help to explain the selection for cellular mechanisms to enhance energy metabolism that have occurred in the lineage leading to humans.

    “These findings might help to explain the selection for cellular mechanisms to enhance energy metabolism that have occurred in the lineage leading to humans.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § Materials and Methods

    Phylogenetic independent contrasts were calculated to examine scaling relationships while controlling for the effects of phylogenetic relatedness in the data set.

    “Phylogenetic independent contrasts were also calculated from the data to examine scaling relationships while controlling for the effects of phylogenetic relatedness in the data set (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Discussion

    Part of the increase in transcript levels of CA2 and other glia-expressed genes observed in the human cerebral cortex may be due to relatively greater numbers of these cell types.

    “Given our current results, it is possible that part of the increase in transcript levels of CA2 and other glia-expressed genes observed in the human cerebral cortex is due to relatively greater numbers of these cell types.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Materials and Methods

    RMA line-fitting was used for bivariate data because this method accounts for error in both independent and dependent variables.

    “To determine the exponent of scaling relationships, we used RMA line-fitting to bivariate data because this method accounts for error in both independent and dependent variables (58).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Sokal RR, Rohlf FJ. Biometry: The Principles and Practice of Statistics in Biological Research. San Francisco: Freeman; 1995. [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Carbonic anhydrases are expressed in glial cells and are involved in modulating CO2 and other metabolic end products to levels that may enable buffering/secretion of lactate.

    “Carbonic anhydrases are expressed in glial cells and are involved in modulating CO2 and other metabolic end products to levels that may enable buffering/secretion of lactate (37, 39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Ames A., III Brain Res Rev. 2000;34:42–68. doi: 10.1016/s0165-0173(00)00038-2. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Materials and Methods

    Neurons were distinguished from glia and endothelial cells by the presence of dark, coarsely stained Nissl substance in the cytoplasm, a large nucleus, a distinct nucleolus, and lightly stained proximal segments of dendritic processes.

    “Based on Nissl-stained sections, neurons were distinguished from glia and endothelial cells by the presence of dark, coarsely stained Nissl substance in the cytoplasm, a large nucleus, a distinct nucleolus, and lightly stained proximal segments of dendritic processes (Fig. 2).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Materials and Methods

    Cellular densities were corrected for shrinkage from histological processing by the number-weighted mean section thickness.

    “Cellular densities (Nv) were derived from these stereologic counts and corrected for shrinkage from histological processing by the number-weighted mean section thickness as described in Sherwood et al. (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Sherwood CC, Raghanti MA, Stimpson CD, Bonar CJ, de Sousa AA, Preuss TM, Hof PR. Brain Behav Evol. in press. [DOI] [PubMed]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning
    § Discussion

    These neurons may also be preferentially vulnerable to alterations of energy metabolism that occur in many age-related degenerative brain illnesses.

    “These neurons may also be preferentially vulnerable to alterations of energy metabolism that occur in many age-related degenerative brain illnesses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation
    § Materials and Methods

    The homologous cortical area 9L could be unambiguously identified across species upon histological observation, and stereologic counts of cell densities were confined to its borders.

    “Therefore, we were able to unambiguously identify this homologous cortical area across species upon histological observation, and our stereologic counts of cell densities were confined to its borders.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation
    § Materials and Methods

    The average coefficient of error of the optical disector analyses was 0.085 ± 0.018 (mean ± SD).

    “On average, the coefficient of error (56) of optical disector analyses was 0.085 ± 0.018 (mean ± SD).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given
    § Materials and Methods

    None of the brain samples used showed evidence of neuropathological abnormality on routine examination.

    “None of the brain samples showed evidence of neuropathological abnormality on routine examination.”
    Quote in the paperSubstantial claim
31 of 31

  • The paper relies on this without support.

    The human brain is approximately three times larger than that of great apes.

    “Because the human brain is approximately three times larger than that of great apes”

  • The paper relies on this without support.

    Area 9L of dorsolateral prefrontal cortex is involved in working memory.

    “within a region of the dorsolateral prefrontal cortex (area 9L) that is involved in “working memory.””

  • The paper relies on this without support.

    The neocortex is functionally and architecturally heterogeneous.

    “because the neocortex is functionally and architecturally heterogeneous”

  • The paper relies on this without support.

    Oligodendrocytes synthesize the myelin that ensheathes axons in the brain to facilitate long-range propagation of action potentials.

    “The other main type of glial cell, oligodendrocytes, synthesize the myelin that ensheathes axons in the brain to facilitate long-range propagation of action potentials.”

  • The paper relies on this without support.

    Regional variation in the glia–neuron ratio of the frontal cortex reflects regional variation in the energetics of that cortex.

    “This finding suggests that regional differences in the energetics of frontal cortex have been largely conserved over ≈25 million years of catarrhine evolution since the last common ancestor shared by macaques and humans.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the gray matter of the cerebral cortex, glial cells outnumber neurons by less than a factor of 2.

    “In the gray matter of the cerebral cortex, glial cells outnumber neurons by a factor of <2 (Sherwood et al., 2006; Pelvig et al., 2008).”

    From The human brain in numbers: a linearly scaled-up primate brain (2009) · cites this paper as Sherwood et al., 2006

    Table 2 (Results; page unavailable) reports glia–neuron ratios below 2 in several sampled frontal-cortex areas, including 1.65 in human area 9L. But the ratio is 2.19 in human area 4, and some sampled ratios are below 1, so the paper does not establish that glia outnumber neurons by a factor of less than 2 throughout cerebral cortical gray matter. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • In nonhuman primates and humans, glial cells seem to somewhat outnumber neurons in the PFC, with regional variation likely contributing to formation of secondary and tertiary gyri.

    “In nonhuman primates and human, glial cells seem to somewhat outnumber neurons in the PFC, albeit with regional variation which is likely to contribute to the formation of secondary and tertiary gyri [77–81].”

    From Development of prefrontal cortex (2022) · cites this paper as [78]

    Results (Tables 1 and 2; page unavailable) show regional variation in frontal-cortex glia–neuron ratios and ratios above 1 in humans and some nonhuman primates. But glia do not outnumber neurons in every nonhuman primate or region examined, and the paper does not link that variation to the formation of secondary or tertiary gyri. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. RL Holloway Gen Syst 12, 3–19 (1967).
  2. CC Sherwood MA Raghanti CD Stimpson CJ Bonar AA de Sousa TM Preuss PR Hof Brain Behav Evol in press.

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Authors
Sherwood, C. C., Stimpson, C. D., Raghanti, M. A., Wildman, D. E., Uddin, M., Grossman, L. I., Goodman, M., Redmond, J. C., Bonar, C. J., Erwin, J. M., & Hof, P. R.
Affiliations
  • George Washington University (US)
  • Kent State University (US)
  • National Institutes of Health (US)
  • Center for Molecular Medicine and Genetics and
  • Wayne State University (US)
  • Emory University (US)
  • Cleveland Metroparks Zoo (US)
  • Foundation for Comparative and Conservation Biology, Needmore, PA 17238;
  • New York Consortium in Evolutionary Primatology (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-09-12
Volume
103
Issue
37
Pages
13606-13611
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0605843103
PMC
PMC1564260
OpenAlex
W2077596732
Semantic Scholar
407b0e61648c4684cd3268e07ecb1c6f9d46ac3f
Cited by
342
References
67
Citations by year
2026: 9 · 2025: 12 · 2024: 7 · 2023: 14 · 2022: 25 · 2021: 21 · 2020: 11 · 2019: 17 · 2018: 21 · 2017: 19 · 2016: 27 · 2015: 22 · 2014: 25 · 2013: 24 · 2012: 18
FWCI
20.71
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (0550209, 0515484, 0549117)
  • James S. McDonnell Foundation (22002078)
  • Wenner-Gren Foundation
  • Northwestern University (AG13854)
  • National Institute on Aging (P30AG13854, P30AG013854)
Topics
  • Social Sciences › Psychology › Social Psychology › Primate Behavior and Ecology
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
human frontal cortex, allometric scaling, dorsolateral prefrontal cortex, chimpanzees, macaque, hominoid evolution, theory of mind, language, brain size
MeSH terms
Animals, Brain, Cell Count, Pan troglodytes, Biological Evolution, Frontal Lobe, Humans, Macaca, Neuroglia, Neurons, Organ Size

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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