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1.  Cellular Scaling Rules of Insectivore Brains 
Insectivores represent extremes in mammalian body size and brain size, retaining various “primitive” morphological characteristics, and some species of Insectivora are thought to share similarities with small-bodied ancestral eutherians. This raises the possibility that insectivore brains differ from other taxa, including rodents and primates, in cellular scaling properties. Here we examine the cellular scaling rules for insectivore brains and demonstrate that insectivore scaling rules overlap somewhat with those for rodents and primates such that the insectivore cortex shares scaling rules with rodents (increasing faster in size than in numbers of neurons), but the insectivore cerebellum shares scaling rules with primates (increasing isometrically). Brain structures pooled as “remaining areas” appear to scale similarly across all three mammalian orders with respect to numbers of neurons, and the numbers of non-neurons appear to scale similarly across all brain structures for all three orders. Therefore, common scaling rules exist, to different extents, between insectivore, rodent, and primate brain regions, and it is hypothesized that insectivores represent the common aspects of each order. The olfactory bulbs of insectivores, however, offer a noteworthy exception in that neuronal density increases linearly with increasing structure mass. This implies that the average neuronal cell size decreases with increasing olfactory bulb mass in order to accommodate greater neuronal density, and represents the first documentation of a brain structure gaining neurons at a greater rate than mass. This might allow insectivore brains to concentrate more neurons within the olfactory bulbs without a prohibitively large and metabolically costly increase in structure mass.
PMCID: PMC2713736  PMID: 19636383
allometry; brain size; comparative neuroanatomy; glia; neurons; evolution; olfactory bulb
2.  Gorilla and Orangutan Brains Conform to the Primate Cellular Scaling Rules: Implications for Human Evolution 
Brain, Behavior and Evolution  2011;77(1):33-44.
Gorillas and orangutans are primates at least as large as humans, but their brains amount to about one third of the size of the human brain. This discrepancy has been used as evidence that the human brain is about 3 times larger than it should be for a primate species of its body size. In contrast to the view that the human brain is special in its size, we have suggested that it is the great apes that might have evolved bodies that are unusually large, on the basis of our recent finding that the cellular composition of the human brain matches that expected for a primate brain of its size, making the human brain a linearly scaled-up primate brain in its number of cells. To investigate whether the brain of great apes also conforms to the primate cellular scaling rules identified previously, we determine the numbers of neuronal and other cells that compose the orangutan and gorilla cerebella, use these numbers to calculate the size of the brain and of the cerebral cortex expected for these species, and show that these match the sizes described in the literature. Our results suggest that the brains of great apes also scale linearly in their numbers of neurons like other primate brains, including humans. The conformity of great apes and humans to the linear cellular scaling rules that apply to other primates that diverged earlier in primate evolution indicates that prehistoric Homo species as well as other hominins must have had brains that conformed to the same scaling rules, irrespective of their body size. We then used those scaling rules and published estimated brain volumes for various hominin species to predict the numbers of neurons that composed their brains. We predict that Homo heidelbergensis and Homo neanderthalensis had brains with approximately 80 billion neurons, within the range of variation found in modern Homo sapiens. We propose that while the cellular scaling rules that apply to the primate brain have remained stable in hominin evolution (since they apply to simians, great apes and modern humans alike), the Colobinae and Pongidae lineages favored marked increases in body size rather than brain size from the common ancestor with the Homo lineage, while the Homo lineage seems to have favored a large brain instead of a large body, possibly due to the metabolic limitations to having both.
PMCID: PMC3064932  PMID: 21228547
Allometry; Brain size; Great apes; Human; Evolution, human; Neurons, number
3.  Updated Neuronal Scaling Rules for the Brains of Glires (Rodents/Lagomorphs) 
Brain, Behavior and Evolution  2011;78(4):302-314.
Brain size scales as different functions of its number of neurons across mammalian orders such as rodents, primates, and insectivores. In rodents, we have previously shown that, across a sample of 6 species, from mouse to capybara, the cerebral cortex, cerebellum and the remaining brain structures increase in size faster than they gain neurons, with an accompanying decrease in neuronal density in these structures [Herculano-Houzel et al.: Proc Natl Acad Sci USA 2006;103:12138–12143]. Important remaining questions are whether such neuronal scaling rules within an order apply equally to all pertaining species, and whether they extend to closely related taxa. Here, we examine whether 4 other species of Rodentia, as well as the closely related rabbit (Lagomorpha), conform to the scaling rules identified previously for rodents. We report the updated neuronal scaling rules obtained for the average values of each species in a way that is directly comparable to the scaling rules that apply to primates [Gabi et al.: Brain Behav Evol 2010;76:32–44], and examine whether the scaling relationships are affected when phylogenetic relatedness in the dataset is accounted for. We have found that the brains of the spiny rat, squirrel, prairie dog and rabbit conform to the neuronal scaling rules that apply to the previous sample of rodents. The conformity to the previous rules of the new set of species, which includes the rabbit, suggests that the cellular scaling rules we have identified apply to rodents in general, and probably to Glires as a whole (rodents/lagomorphs), with one notable exception: the naked mole-rat brain is apparently an outlier, with only about half of the neurons expected from its brain size in its cerebral cortex and cerebellum.
PMCID: PMC3237106  PMID: 21985803
Rodents; Brain size; Evolution; Neurons; Glia; Glires
4.  Cellular scaling rules for the brain of Artiodactyla include a highly folded cortex with few neurons 
Quantitative analysis of the cellular composition of rodent, primate, insectivore, and afrotherian brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of artiodactyls, a group within the order Cetartiodactyla, believed to be a relatively recent radiation from the common Eutherian ancestor. We find that artiodactyls share non-neuronal scaling rules with all groups analyzed previously. Artiodactyls share with afrotherians and rodents, but not with primates, the neuronal scaling rules that apply to the cerebral cortex and cerebellum. The neuronal scaling rules that apply to the remaining brain areas are, however, distinct in artiodactyls. Importantly, we show that the folding index of the cerebral cortex scales with the number of neurons in the cerebral cortex in distinct fashions across artiodactyls, afrotherians, rodents, and primates, such that the artiodactyl cerebral cortex is more convoluted than primate cortices of similar numbers of neurons. Our findings suggest that the scaling rules found to be shared across modern afrotherians, glires, and artiodactyls applied to the common Eutherian ancestor, such as the relationship between the mass of the cerebral cortex as a whole and its number of neurons. In turn, the distribution of neurons along the surface of the cerebral cortex, which is related to its degree of gyrification, appears to be a clade-specific characteristic. If the neuronal scaling rules for artiodactyls extend to all cetartiodactyls, we predict that the large cerebral cortex of cetaceans will still have fewer neurons than the human cerebral cortex.
PMCID: PMC4228855  PMID: 25429261
evolution; cortical expansion; numbers of neurons; gyrification; brain size
5.  The Evolution of Brains from Early Mammals to Humans 
The large size and complex organization of the human brain makes it unique among primate brains. In particular, the neocortex constitutes about 80% of the brain, and this cortex is subdivided into a large number of functionally specialized regions, the cortical areas. Such a brain mediates accomplishments and abilities unmatched by any other species. How did such a brain evolve? Answers come from comparative studies of the brains of present-day mammals and other vertebrates in conjunction with information about brain sizes and shapes from the fossil record, studies of brain development, and principles derived from studies of scaling and optimal design. Early mammals were small, with small brains, an emphasis on olfaction, and little neocortex. Neocortex was transformed from the single layer of output pyramidal neurons of the dorsal cortex of earlier ancestors to the six layers of all present-day mammals. This small cap of neocortex was divided into 20–25 cortical areas, including primary and some of the secondary sensory areas that characterize neocortex in nearly all mammals today. Early placental mammals had a corpus callosum connecting the neocortex of the two hemispheres, a primary motor area, M1, and perhaps one or more premotor areas. One line of evolution, Euarchontoglires, led to present-day primates, tree shrews, flying lemurs, rodents and rabbits. Early primates evolved from small-brained, nocturnal, insect-eating mammals with an expanded region of temporal visual cortex. These early nocturnal primates were adapted to the fine branch niche of the tropical rainforest by having an even more expanded visual system that mediated visually guided reaching and grasping of insects, small vertebrates, and fruits. Neocortex was greatly expanded, and included an array of cortical areas that characterize neocortex of all living primates. Specializations of the visual system included new visual areas that contributed to a dorsal stream of visuomotor processing in a greatly enlarged region of posterior parietal cortex and an expanded motor system and the addition of a ventral premotor area. Higher visual areas in a large temporal lobe facilitated object recognition, and frontal cortex, included granular prefrontal cortex. Auditory cortex included the primary and secondary auditory areas that characterize prosimian and anthropoid primates today. As anthropoids emerged as diurnal primates, the visual system specialized for detailed foveal vision. Other adaptations included an expansion of prefrontal cortex and insular cortex. The human and chimpanzee-bonobo lineages diverged some 6–8 million years ago with brains that were about one-third the size of modern humans. Over the last two million years, the brains of our more recent ancestors increased greatly in size, especially in the prefrontal, posterior parietal, lateral temporal, and insular regions. Specialization of the two cerebral hemispheres for related, but different functions became pronounced, and language and other impressive cognitive abilities emerged.
PMCID: PMC3606080  PMID: 23529256
6.  The elephant brain in numbers 
What explains the superior cognitive abilities of the human brain compared to other, larger brains? Here we investigate the possibility that the human brain has a larger number of neurons than even larger brains by determining the cellular composition of the brain of the African elephant. We find that the African elephant brain, which is about three times larger than the human brain, contains 257 billion (109) neurons, three times more than the average human brain; however, 97.5% of the neurons in the elephant brain (251 billion) are found in the cerebellum. This makes the elephant an outlier in regard to the number of cerebellar neurons compared to other mammals, which might be related to sensorimotor specializations. In contrast, the elephant cerebral cortex, which has twice the mass of the human cerebral cortex, holds only 5.6 billion neurons, about one third of the number of neurons found in the human cerebral cortex. This finding supports the hypothesis that the larger absolute number of neurons in the human cerebral cortex (but not in the whole brain) is correlated with the superior cognitive abilities of humans compared to elephants and other large-brained mammals.
PMCID: PMC4053853  PMID: 24971054
elephant; cerebral cortex; numbers of neurons; neuronal density; cerebellum; glia/neuron ratio; brain size
7.  Cellular Scaling Rules for the Brains of an Extended Number of Primate Species 
Brain, Behavior and Evolution  2010;76(1):32-44.
What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size.
PMCID: PMC2980814  PMID: 20926854
Allometry; Brain size; Evolution; Glia, number; Neurons, number; Primates
8.  Greater addition of neurons to the olfactory bulb than to the cerebral cortex of eulipotyphlans but not rodents, afrotherians or primates 
The olfactory bulb is an evolutionarily old structure that antedates the appearance of a six-layered mammalian cerebral cortex. As such, the neuronal scaling rules that apply to scaling the mass of the olfactory bulb as a function of its number of neurons might be shared across mammalian groups, as we have found to be the case for the ensemble of non-cortical, non-cerebellar brain structures. Alternatively, the neuronal scaling rules that apply to the olfactory bulb might be distinct in those mammals that rely heavily on olfaction. The group previously referred to as Insectivora includes small mammals, some of which are now placed in Afrotheria, a base group in mammalian radiation, and others in Eulipotyphla, a group derived later, at the base of Laurasiatheria. Here we show that the neuronal scaling rules that apply to building the olfactory bulb differ across eulipotyphlans and other mammals such that eulipotyphlans have more neurons concentrated in an olfactory bulb of similar size than afrotherians, glires and primates. Most strikingly, while the cerebral cortex gains neurons at a faster pace than the olfactory bulb in glires, and afrotherians follow this trend, it is the olfactory bulb that gains neurons at a faster pace than the cerebral cortex in eulipotyphlans, which contradicts the common view that the cerebral cortex is the fastest expanding structure in brain evolution. Our findings emphasize the importance of not using brain structure size as a proxy for numbers of neurons across mammalian orders, and are consistent with the notion that different selective pressures have acted upon the olfactory system of eulipotyphlans, glires and primates, with eulipotyphlans relying more on olfaction for their behavior than glires and primates. Surprisingly, however, the neuronal scaling rules for primates predict that the human olfactory bulb has as many neurons as the larger eulipotyphlan olfactory bulbs, which questions the classification of humans as microsmatic.
PMCID: PMC3990053  PMID: 24782719
olfactory bulb; cortical expansion; mosaic evolution; olfaction
9.  Cellular scaling rules for the brain of afrotherians 
Quantitative analysis of the cellular composition of rodent, primate and eulipotyphlan brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in evolution in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of afrotherians, believed to be the first clade to radiate from the common eutherian ancestor. We find that afrotherians share non-neuronal scaling rules with rodents, primates and eulipotyphlans, as well as the coordinated scaling of numbers of neurons in the cerebral cortex and cerebellum. Afrotherians share with rodents and eulipotyphlans, but not with primates, the scaling of number of neurons in the cortex and in the cerebellum as a function of the number of neurons in the rest of the brain. Afrotheria also share with rodents and eulipotyphlans the neuronal scaling rules that apply to the cerebral cortex. Afrotherians share with rodents, but not with eulipotyphlans nor primates, the neuronal scaling rules that apply to the cerebellum. Importantly, the scaling of the folding index of the cerebral cortex with the number of neurons in the cerebral cortex is not shared by either afrotherians, rodents, or primates. The sharing of some neuronal scaling rules between afrotherians and rodents, and of some additional features with eulipotyphlans and primates, raise the interesting possibility that these shared characteristics applied to the common eutherian ancestor. In turn, the clade-specific characteristics that relate to the distribution of neurons along the surface of the cerebral cortex and to its degree of gyrification suggest that these characteristics compose an evolutionarily plastic suite of features that may have defined and distinguished mammalian groups in evolution.
PMCID: PMC3925844  PMID: 24596544
evolution; glia-neuron ratio; numbers of neurons; cortical expansion; gyrification
10.  Comparative neuronal morphology of the cerebellar cortex in afrotherians, carnivores, cetartiodactyls, and primates 
Although the basic morphological characteristics of neurons in the cerebellar cortex have been documented in several species, virtually nothing is known about the quantitative morphological characteristics of these neurons across different taxa. To that end, the present study investigated cerebellar neuronal morphology among eight different, large-brained mammalian species comprising a broad phylogenetic range: afrotherians (African elephant, Florida manatee), carnivores (Siberian tiger, clouded leopard), cetartiodactyls (humpback whale, giraffe) and primates (human, common chimpanzee). Specifically, several neuron types (e.g., stellate, basket, Lugaro, Golgi, and granule neurons; N = 317) of the cerebellar cortex were stained with a modified rapid Golgi technique and quantified on a computer-assisted microscopy system. There was a 64-fold variation in brain mass across species in our sample (from clouded leopard to the elephant) and a 103-fold variation in cerebellar volume. Most dendritic measures tended to increase with cerebellar volume. The cerebellar cortex in these species exhibited the trilaminate pattern common to all mammals. Morphologically, neuron types in the cerebellar cortex were generally consistent with those described in primates (Fox et al., 1967) and rodents (Palay and Chan-Palay, 1974), although there was substantial quantitative variation across species. In particular, Lugaro neurons in the elephant appeared to be disproportionately larger than those in other species. To explore potential quantitative differences in dendritic measures across species, MARSplines analyses were used to evaluate whether species could be differentiated from each other based on dendritic characteristics alone. Results of these analyses indicated that there were significant differences among all species in dendritic measures.
PMCID: PMC4005950  PMID: 24795574
dendrite; morphometry; Golgi method; brain evolution; cerebellum
11.  Quantitative relationships in delphinid neocortex 
Possessing large brains and complex behavioral patterns, cetaceans are believed to be highly intelligent. Their brains, which are the largest in the Animal Kingdom and have enormous gyrification compared with terrestrial mammals, have long been of scientific interest. Few studies, however, report total number of brain cells in cetaceans, and even fewer have used unbiased counting methods. In this study, using stereological methods, we estimated the total number of cells in the neocortex of the long-finned pilot whale (Globicephala melas) brain. For the first time, we show that a species of dolphin has more neocortical neurons than any mammal studied to date including humans. These cell numbers are compared across various mammals with different brain sizes, and the function of possessing many neurons is discussed. We found that the long-finned pilot whale neocortex has approximately 37.2 × 109 neurons, which is almost twice as many as humans, and 127 × 109 glial cells. Thus, the absolute number of neurons in the human neocortex is not correlated with the superior cognitive abilities of humans (at least compared to cetaceans) as has previously been hypothesized. However, as neuron density in long-finned pilot whales is lower than that in humans, their higher cell number appears to be due to their larger brain. Accordingly, our findings make an important contribution to the ongoing debate over quantitative relationships in the mammalian brain.
PMCID: PMC4244864  PMID: 25505387
neocortical cell number; glia/neuron ratio; neocortical cell density; animal cognition; stereology
12.  An Adaptive Threshold in Mammalian Neocortical Evolution 
PLoS Biology  2014;12(11):e1002000.
A study of the evolutionary history of cortical folding in mammals, its relationship to physiological and life-history traits and the underlying cortical progenitor behavior during embryogenesis, explains the diversity of folding we see across modern mammals. The diversity of neocortical folding among mammals can be explained by two distinct neurogenic programs, which give rise to mammals with a highly folded neocortex and mammals with slightly folded or unfolded neocortex, each occupying a distinct ecological niche.
Expansion of the neocortex is a hallmark of human evolution. However, determining which adaptive mechanisms facilitated its expansion remains an open question. Here we show, using the gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We find that variation in GI does not evolve linearly across species, but that mammals constitute two principal groups above and below a GI threshold value of 1.5, approximately equal to 109 neurons, which may be characterized by distinct constellations of physiological and life-history traits. By integrating data on neurogenic period, neuroepithelial founder pool size, cell-cycle length, progenitor-type abundances, and cortical neuron number into discrete mathematical models, we identify symmetric proliferative divisions of basal progenitors in the subventricular zone of the developing neocortex as evolutionarily necessary for generating a 14-fold increase in daily prenatal neuron production, traversal of the GI threshold, and thus establishment of two principal groups. We conclude that, despite considerable neuroanatomical differences, changes in the length of the neurogenic period alone, rather than any novel neurogenic progenitor lineage, are sufficient to explain differences in neuron number and neocortical size between species within the same principal group.
Author Summary
What are the key differences in the development and evolution of the cerebral cortex that underlie the differences in its size and degree of folding across mammals? Here, we present phylogenetic evidence that the Jurassic era mammalian ancestor may have been a relatively large-brained species with a folded neocortex. We then show that variation in the degree of cortical folding (gyrencephaly index [GI]) does not evolve linearly across species, as previously assumed, but that mammals fall into two principal groups associated with distinct ecological niches: low-GI mammals (such as mice and tarsiers) and high-GI mammals (such as dolphins and humans), which are found to generate on average 14-fold more brain weight per day of gestation. This greater daily brain weight production in mammals with a highly folded neocortex requires a specific class of progenitor cell-type to adopt a special mode of cell division, which is absent in mammals with slightly folded or unfolded neocortices. Differences among mammals within the same GI group (high or low) are not due to different programming, but rather the result of differences in the length of the neurogenic period. So, the impressively large and folded human neocortex, which is three times the size of the chimpanzee neocortex, can be explained by a modest evolutionary extension of the neurogenic period with respect to its closest primate ancestors.
PMCID: PMC4236020  PMID: 25405475
13.  Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution 
PLoS ONE  2011;6(3):e17514.
It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.
PMCID: PMC3046985  PMID: 21390261
14.  Spatio-temporal extension in site of origin for cortical calretinin neurons in primates 
The vast majority of cortical GABAergic neurons can be defined by parvalbumin, somatostatin or calretinin expression. In most mammalians, parvalbumin and somatostatin interneurons have constant proportions, each representing 5–7% of the total neuron number. In contrast, there is a threefold increase in the proportion of calretinin interneurons, which do not exceed 4% in rodents and reach 12% in higher order areas of primate cerebral cortex. In rodents, almost all parvalbumin and somatostatin interneurons originate from the medial part of the subpallial proliferative structure, the ganglionic eminence (GE), while almost all calretinin interneurons originate from its caudal part. The spatial pattern of cortical GABAergic neurons origin from the GE is preserved in the monkey and human brain. However, it could be expected that the evolution is changing developmental rules to enable considerable expansion of calretinin interneuron population. During the early fetal period in primates, cortical GABAergic neurons are almost entirely generated in the subpallium, as in rodents. Already at that time, the primate caudal ganglionic eminence (CGE) shows a relative increase in size and production of calretinin interneurons. During the second trimester of gestation, that is the main neurogenetic stage in primates without clear correlates found in rodents, the pallial production of cortical GABAergic neurons together with the extended persistence of the GE is observed. We propose that the CGE could be the main source of calretinin interneurons for the posterior and lateral cortical regions, but not for the frontal cortex. The associative granular frontal cortex represents around one third of the cortical surface and contains almost half of cortical calretinin interneurons. The majority of calretinin interneurons destined for the frontal cortex could be generated in the pallium, especially in the newly evolved outer subventricular zone that becomes the main pool of cortical progenitors.
PMCID: PMC4072090  PMID: 25018702
interneurons; calretinin; ganglionic eminence; ventricular zone; GABA; epilepsy
15.  Brain scaling in mammalian evolution as a consequence of concerted and mosaic changes in numbers of neurons and average neuronal cell size 
Enough species have now been subject to systematic quantitative analysis of the relationship between the morphology and cellular composition of their brain that patterns begin to emerge and shed light on the evolutionary path that led to mammalian brain diversity. Based on an analysis of the shared and clade-specific characteristics of 41 modern mammalian species in 6 clades, and in light of the phylogenetic relationships among them, here we propose that ancestral mammal brains were composed and scaled in their cellular composition like modern afrotherian and glire brains: with an addition of neurons that is accompanied by a decrease in neuronal density and very little modification in glial cell density, implying a significant increase in average neuronal cell size in larger brains, and the allocation of approximately 2 neurons in the cerebral cortex and 8 neurons in the cerebellum for every neuron allocated to the rest of brain. We also propose that in some clades the scaling of different brain structures has diverged away from the common ancestral layout through clade-specific (or clade-defining) changes in how average neuronal cell mass relates to numbers of neurons in each structure, and how numbers of neurons are differentially allocated to each structure relative to the number of neurons in the rest of brain. Thus, the evolutionary expansion of mammalian brains has involved both concerted and mosaic patterns of scaling across structures. This is, to our knowledge, the first mechanistic model that explains the generation of brains large and small in mammalian evolution, and it opens up new horizons for seeking the cellular pathways and genes involved in brain evolution.
PMCID: PMC4127475  PMID: 25157220
numbers of neurons; brain size; cortical expansion; evolution; cell size
16.  The von Economo neurons in fronto-insular and anterior cingulate cortex 
The von Economo neurons (VENs) are large bipolar neurons located in fronto-insular cortex (FI) and anterior limbic area (LA) in great apes and humans but not in other primates. Our stereological counts of VENs in FI and LA show them to be more numerous in humans than in apes. In humans, small numbers of VENs appear the 36th week post conception, with numbers increasing during the first eight months after birth. There are significantly more VENs in the right hemisphere in postnatal brains; this may be related to asymmetries in the autonomic nervous system. VENs are also present in elephants and whales and may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI and LA to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of fronto-temporal dementia implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging.
PMCID: PMC3140770  PMID: 21534993
fronto-temporal dementia; autism; schizophrenia; empathy; disgust; self-awareness; hemispheric specialization
17.  Coordinated Scaling of Cortical and Cerebellar Numbers of Neurons 
While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.
PMCID: PMC2839851  PMID: 20300467
brain size; brain scaling; mosaic evolution; numbers of neurons; cerebral cortex; cerebellum
18.  A volumetric comparison of the insular cortex and its subregions in primates 
Journal of human evolution  2013;64(4):263-279.
The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body’s homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.
PMCID: PMC3756831  PMID: 23466178
Allometry; Brain; Evolution; Frontoinsular cortex; Hominoids
19.  Evolutionary appearance of von Economo’s neurons in the mammalian cerebral cortex 
von Economo’s neurons (VENs) are large, spindle-shaped projection neurons in layer V of the frontoinsular (FI) cortex, and the anterior cingulate cortex. During human ontogenesis, the VENs can first be differentiated at late stages of gestation, and increase in number during the first eight postnatal months. VENs have been identified in humans, chimpanzee, bonobos, gorillas, orangutan and, more recently, in the macaque. Their distribution in great apes seems to correlate with human-like social cognitive abilities and self-awareness. VENs are also found in whales, in a number of different cetaceans, and in the elephant. This phylogenetic distribution may suggest a correlation among the VENs, brain size and the “social brain.” VENs may be involved in the pathogenesis of specific neurological and psychiatric diseases, such as autism, callosal agenesis and schizophrenia. VENs are selectively affected in a behavioral variant of frontotemporal dementia in which empathy, social awareness and self-control are seriously compromised, thus associating VENs with the social brain. However, the presence of VENs has also been related to special functions such as mirror self-recognition. Areas containing VENs have been related to motor awareness or sense-of-knowing, discrimination between self and other, and between self and the external environment. Along this line, VENs have been related to the “global Workspace” architecture: in accordance the VENs have been correlated to emotional and interoceptive signals by providing fast connections (large axons = fast communication) between salience-related insular and cingulate and other widely separated brain areas. Nevertheless, the lack of a characterization of their physiology and anatomical connectivity allowed only to infer their functional role based on their location and on the functional magnetic resonance imaging data. The recent finding of VENs in the anterior insula of the macaque opens the way to new insights and experimental investigations.
PMCID: PMC3953677  PMID: 24672457
insula; cingulate cortex; salience network; self-awareness; prediction; development
20.  Evolutionary conservation in genes underlying human psychiatric disorders 
Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained.
PMCID: PMC4018557  PMID: 24834046
schizophrenia; autism; Homo sapiens; adaptation
21.  The evolution of the complex sensory and motor systems of the human brain 
Brain research bulletin  2007;75(2-4):384-390.
Inferences about how the complex sensory and motor systems of the human brain evolved are based on the results of comparative studies of brain organization across a range of mammalian species, and evidence from the endocasts of fossil skulls of key extinct species. The endocasts of the skulls of early mammals indicate that they had small brains with little neocortex. Evidence from comparative studies of cortical organization from small-brained mammals of the six major branches of mammalian evolution supports the conclusion that the small neocortex of early mammals was divided into roughly 20–25 cortical areas, including primary and secondary sensory fields. In early primates, vision was the dominant sense, and cortical areas associated with vision in temporal and occipital cortex underwent a significant expansion. Comparative studies indicate that early primates had 10 or more visual areas, and somatosensory areas with expanded representations of the forepaw. Posterior parietal cortex was also expanded, with a caudal half dominated by visual inputs, and a rostral half dominated by somatosensory inputs with outputs to an array of seven or more motor and visuomotor areas of the frontal lobe. Somatosensory areas and posterior parietal cortex became further differentiated in early anthropoid primates. As larger brains evolved in early apes and in our hominin ancestors, the number of cortical areas increased to reach an estimated 200 or so in present day humans, and hemispheric specializations emerged. The large human brain grew primarily by increasing neuron number rather than increasing average neuron size.
PMCID: PMC2349093  PMID: 18331903
22.  Faster scaling of visual neurons in cortical areas relative to subcortical structures in non-human primate brains 
Brain structure & function  2012;218(3):805-816.
Cortical expansion, both in absolute terms and in relation to subcortical structures, is considered a major trend in mammalian brain evolution with important functional implications, given that cortical computations should add complexity and flexibility to information processing. Here, we investigate the numbers of neurons that compose 4 structures in the visual pathway across 11 non-human primate species to determine the scaling relationships that apply to these structures and among them. We find that primary visual cortex, area V1, as well as the superior colliculus (SC) and lateral geniculate nucleus scale in mass faster than they gain neurons. Areas V1 and MT gain neurons proportionately to the entire cerebral cortex, and represent fairly constant proportions of all cortical neurons (36 and 3 %, respectively), while V1 gains neurons much faster than both subcortical structures examined. Larger primate brains therefore have increased ratios of cortical to subcortical neurons involved in processing visual information, as observed in the auditory pathway, but have a constant proportion of cortical neurons dedicated to the primary visual representation, and a fairly constant ratio of about 45 times more neurons in primary visual than in primary auditory cortical areas.
PMCID: PMC3727908  PMID: 22684638
Superior colliculus; Visual cortex; Lateral geniculate nucleus; V1; Area MT; Thalamus; Allometry; Brain size; Evolution
23.  Evolution of the human brain: when bigger is better 
Comparative studies of the brain in mammals suggest that there are general architectural principles governing its growth and evolutionary development. We are beginning to understand the geometric, biophysical and energy constraints that have governed the evolution and functional organization of the brain and its underlying neuronal network. The object of this review is to present current perspectives on primate brain evolution, especially in humans, and to examine some hypothetical organizing principles that underlie the brain's complex organization. Some of the design principles and operational modes that underlie the information processing capacity of the cerebral cortex in primates will be explored. It is shown that the development of the cortex coordinates folding with connectivity in a way that produces smaller and faster brains, then otherwise would have been possible. In view of the central importance placed on brain evolution in explaining the success of our own species, one may wonder whether there are physical limits that constrain its processing power and evolutionary potential. It will be argued that at a brain size of about 3500 cm3, corresponding to a brain volume two to three times that of modern man, the brain seems to reach its maximum processing capacity. The larger the brain grows beyond this critical size, the less efficient it will become, thus limiting any improvement in cognitive power.
PMCID: PMC3973910  PMID: 24723857
brain evolution; cerebral cortex; cortical design; neural networks; information processing; intelligence; primates; human neocortex
24.  A Neural Circuit Covarying with Social Hierarchy in Macaques 
PLoS Biology  2014;12(9):e1001940.
A neural circuit that covaries with social hierarchy A neuroimaging study reveals that individual variation in brain circuits in structures below the cerebral cortex of macaques is associated with experience at different ends of the social hierarchy.
Despite widespread interest in social dominance, little is known of its neural correlates in primates. We hypothesized that social status in primates might be related to individual variation in subcortical brain regions implicated in other aspects of social and emotional behavior in other mammals. To examine this possibility we used magnetic resonance imaging (MRI), which affords the taking of quantitative measurements noninvasively, both of brain structure and of brain function, across many regions simultaneously. We carried out a series of tests of structural and functional MRI (fMRI) data in 25 group-living macaques. First, a deformation-based morphometric (DBM) approach was used to show that gray matter in the amygdala, brainstem in the vicinity of the raphe nucleus, and reticular formation, hypothalamus, and septum/striatum of the left hemisphere was correlated with social status. Second, similar correlations were found in the same areas in the other hemisphere. Third, similar correlations were found in a second data set acquired several months later from a subset of the same animals. Fourth, the strength of coupling between fMRI-measured activity in the same areas was correlated with social status. The network of subcortical areas, however, had no relationship with the sizes of individuals' social networks, suggesting the areas had a simple and direct relationship with social status. By contrast a second circuit in cortex, comprising the midsuperior temporal sulcus and anterior and dorsal prefrontal cortex, covaried with both individuals' social statuses and the social network sizes they experienced. This cortical circuit may be linked to the social cognitive processes that are taxed by life in more complex social networks and that must also be used if an animal is to achieve a high social status.
Author Summary
Social status is an important feature of group life in many primates. Position in the dominance hierarchy influences access to food and mates and is correlated with both general and mental health. Discovering how the brain is organized with respect to individual social status is an important first step for understanding the neural mechanisms that might drive social status and mediate its consequences. We performed a neuroimaging study in non-human primates and our findings suggest that brain organization reflects at least two aspects of dominance. First, we identified neural circuits in brain regions that appear to have a relatively simple and direct relationship with social status—one circuit in which gray matter volume tended to be greater in socially dominant individuals and another in which gray matter volume was greater in those with a more subordinate social position. We also showed that the degree of connectivity within each circuit was associated with experiences at each end of the social hierarchy. Second, given that social status in male macaques depends not only on successful engagement in agonistic behavior but also on success in forming social bonds that promote coalitions, we explored regions where gray matter relates to both social status and social network size. This second neural circuit may mediate the way in which dominance is dependent on social bond formation, which is in turn dependent on social cognition.
PMCID: PMC4151964  PMID: 25180883
25.  Complete morphologies of basal forebrain cholinergic neurons in the mouse 
eLife  2014;3:e02444.
The basal forebrain cholinergic system modulates neuronal excitability and vascular tone throughout the cerebral cortex and hippocampus. This system is severely affected in Alzheimer's disease (AD), and drug treatment to enhance cholinergic signaling is widely used as symptomatic therapy in AD. Defining the full morphologies of individual basal forebrain cholinergic neurons has, until now, been technically beyond reach due to their large axon arbor sizes. Using genetically-directed sparse labeling, we have characterized the complete morphologies of basal forebrain cholinergic neurons in the mouse. Individual arbors were observed to span multiple cortical columns, and to have >1000 branch points and total axon lengths up to 50 cm. In an AD model, cholinergic axons were slowly lost and there was an accumulation of axon-derived material in discrete puncta. Calculations based on published morphometric data indicate that basal forebrain cholinergic neurons in humans have a mean axon length of ∼100 meters.
eLife digest
The human brain is made up of roughly 80 to 100 billion neurons, organized into extensive networks. Each neuron consists of a number of components: a cell body, which contains the nucleus; numerous short protrusions from the cell body called dendrites; and a long thin structure called an axon that carries the electrical signals generated in the cell body and the dendrites to the next neuron in the network.
One of the most studied networks in the human brain is the basal forebrain network, which is made up of large neurons that communicate with one another using a chemical transmitter called acetylcholine. This network has a key role in cognition, and its neurons are among the first to degenerate in Alzheimer's disease. However, relatively little is known about the structure of these ‘cholinergic’ neurons because their large size makes them difficult to study using standard techniques.
Now, Wu et al. have visualized, for the first time, the complete 3D structure of cholinergic neurons in the mouse forebrain. The mice in question had been genetically modified so that only ten or so of their many thousands of cholinergic neurons expressed a distinctive ‘marker’ protein. This made it possible to distinguish these neurons from surrounding brain tissue in order to visualize their structures. The resulting pictures clearly illustrate the neurons' complexity, with individual axons in adult mice displaying up to 1000 branches.
Measurements showed that each cholinergic axon in the mouse brain is roughly 30 centimeters long, even though the brain itself is less than 2 centimeters from front to back. Based on measurements by other researchers, Wu et al. calculated that the axons of single cholinergic neurons in the human brain are about 100 meters long on average.
The extreme length and complex branching structure of cholinergic forebrain neurons helps to explain why each neuron is able to modulate the activity of many others in the network. It could also explain their vulnerability to degeneration, as the need to transport materials over such long distances may limit the ability of these neurons to respond to damage.
PMCID: PMC4038840  PMID: 24894464
Cre; LoxP; Alzheimer's disease; neurodegeneration; cerebral cortex; axon arbor; mouse

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