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1.  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
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.  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
4.  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
5.  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
6.  The Human Brain in Numbers: A Linearly Scaled-up Primate Brain  
The human brain has often been viewed as outstanding among mammalian brains: the most cognitively able, the largest-than-expected from body size, endowed with an overdeveloped cerebral cortex that represents over 80% of brain mass, and purportedly containing 100 billion neurons and 10× more glial cells. Such uniqueness was seemingly necessary to justify the superior cognitive abilities of humans over larger-brained mammals such as elephants and whales. However, our recent studies using a novel method to determine the cellular composition of the brain of humans and other primates as well as of rodents and insectivores show that, since different cellular scaling rules apply to the brains within these orders, brain size can no longer be considered a proxy for the number of neurons in the brain. These studies also showed that the human brain is not exceptional in its cellular composition, as it was found to contain as many neuronal and non-neuronal cells as would be expected of a primate brain of its size. Additionally, the so-called overdeveloped human cerebral cortex holds only 19% of all brain neurons, a fraction that is similar to that found in other mammals. In what regards absolute numbers of neurons, however, the human brain does have two advantages compared to other mammalian brains: compared to rodents, and probably to whales and elephants as well, it is built according to the very economical, space-saving scaling rules that apply to other primates; and, among economically built primate brains, it is the largest, hence containing the most neurons. These findings argue in favor of a view of cognitive abilities that is centered on absolute numbers of neurons, rather than on body size or encephalization, and call for a re-examination of several concepts related to the exceptionality of the human brain.
PMCID: PMC2776484  PMID: 19915731
brain scaling; number of neurons; human; encephalization
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Different scaling of white matter volume, cortical connectivity, and gyrification across rodent and primate brains 
Expansion of the cortical gray matter in evolution has been accompanied by an even faster expansion of the subcortical white matter volume and by folding of the gray matter surface, events traditionally considered to occur homogeneously across mammalian species. Here we investigate how white matter expansion and cortical folding scale across species of rodents and primates as the gray matter gains neurons. We find very different scaling rules of white matter expansion across the two orders, favoring volume conservation and smaller propagation times in primates. For a similar number of cortical neurons, primates have a smaller connectivity fraction and less white matter volume than rodents; moreover, as the cortex gains neurons, there is a much faster increase in white matter volume and in its ratio to gray matter volume in rodents than in primates. Order-specific scaling of the white matter can be attributed to different scaling of average fiber caliber and neuronal connectivity in rodents and primates. Finally, cortical folding increases as different functions of the number of cortical neurons in rodents and primates, scaling faster in the latter than in the former. While the neuronal rules that govern gray and white matter scaling are different across rodents and primates, we find that they can be explained by the same unifying model, with order-specific exponents. The different scaling of the white matter has implications for the scaling of propagation time and computational capacity in evolution, and calls for a reappraisal of developmental models of cortical expansion in evolution.
PMCID: PMC3620553  PMID: 23576961
white matter; number of neurons; allometry; brain size; cortical expansion; gyrification
13.  All brains are made of this: a fundamental building block of brain matter with matching neuronal and glial masses 
How does the size of the glial and neuronal cells that compose brain tissue vary across brain structures and species? Our previous studies indicate that average neuronal size is highly variable, while average glial cell size is more constant. Measuring whole cell sizes in vivo, however, is a daunting task. Here we use chi-square minimization of the relationship between measured neuronal and glial cell densities in the cerebral cortex, cerebellum, and rest of brain in 27 mammalian species to model neuronal and glial cell mass, as well as the neuronal mass fraction of the tissue (the fraction of tissue mass composed by neurons). Our model shows that while average neuronal cell mass varies by over 500-fold across brain structures and species, average glial cell mass varies only 1.4-fold. Neuronal mass fraction varies typically between 0.6 and 0.8 in all structures. Remarkably, we show that two fundamental, universal relationships apply across all brain structures and species: (1) the glia/neuron ratio varies with the total neuronal mass in the tissue (which in turn depends on variations in average neuronal cell mass), and (2) the neuronal mass per glial cell, and with it the neuronal mass fraction and neuron/glia mass ratio, varies with average glial cell mass in the tissue. We propose that there is a fundamental building block of brain tissue: the glial mass that accompanies a unit of neuronal mass. We argue that the scaling of this glial mass is a consequence of a universal mechanism whereby numbers of glial cells are added to the neuronal parenchyma during development, irrespective of whether the neurons composing it are large or small, but depending on the average mass of the glial cells being added. We also show how evolutionary variations in neuronal cell mass, glial cell mass and number of neurons suffice to determine the most basic characteristics of brain structures, such as mass, glia/neuron ratio, neuron/glia mass ratio, and cell densities.
PMCID: PMC4228857  PMID: 25429260
allometry; glia/neuron ratio; number of neurons; number of glial cells; cell size; brain size
14.  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
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.  Visual specialization and brain evolution in primates. 
Several theories have been proposed to explain the evolution of species differences in brain size, but no consensus has emerged. One unresolved question is whether brain size differences are a result of neural specializations or of biological constraints affecting the whole brain. Here I show that, among primates, brain size variation is associated with visual specialization. Primates with large brains for their body size have relatively expanded visual brain areas, including the primary visual cortex and lateral geniculate nucleus. Within the visual system, it is, in particular, one functionally specialized pathway upon which selection has acted: evolutionary changes in the number of neurons in parvocellular, but not magnocellular, layers of the lateral geniculate nucleus are correlated with changes in both brain size and ecological variables (diet and social group size). Given the known functions of the parvocellular pathway, these results suggest that the relatively large brains of frugivorous species are products of selection on the ability to perceive and select fruits using specific visual cues such as colour. The separate correlation between group size and visual brain evolution, on the other hand, may indicate the visual basis of social information processing in the primate brain.
PMCID: PMC1689478  PMID: 9821360
17.  Neocortical Axon Arbors Trade-off Material and Conduction Delay Conservation 
PLoS Computational Biology  2010;6(3):e1000711.
The brain contains a complex network of axons rapidly communicating information between billions of synaptically connected neurons. The morphology of individual axons, therefore, defines the course of information flow within the brain. More than a century ago, Ramón y Cajal proposed that conservation laws to save material (wire) length and limit conduction delay regulate the design of individual axon arbors in cerebral cortex. Yet the spatial and temporal communication costs of single neocortical axons remain undefined. Here, using reconstructions of in vivo labelled excitatory spiny cell and inhibitory basket cell intracortical axons combined with a variety of graph optimization algorithms, we empirically investigated Cajal's conservation laws in cerebral cortex for whole three-dimensional (3D) axon arbors, to our knowledge the first study of its kind. We found intracortical axons were significantly longer than optimal. The temporal cost of cortical axons was also suboptimal though far superior to wire-minimized arbors. We discovered that cortical axon branching appears to promote a low temporal dispersion of axonal latencies and a tight relationship between cortical distance and axonal latency. In addition, inhibitory basket cell axonal latencies may occur within a much narrower temporal window than excitatory spiny cell axons, which may help boost signal detection. Thus, to optimize neuronal network communication we find that a modest excess of axonal wire is traded-off to enhance arbor temporal economy and precision. Our results offer insight into the principles of brain organization and communication in and development of grey matter, where temporal precision is a crucial prerequisite for coincidence detection, synchronization and rapid network oscillations.
Author Summary
Within the grey matter of cerebral cortex is a complex network formed by a dense tangle of individual branching axons mostly of cortical origin. Yet remarkably when presented with a barrage of complex, noisy sensory stimuli this convoluted network architecture computes accurately and rapidly. How does such a highly interconnected though jumbled forest of axonal trees process vital information so quickly? Pioneering neuroscientist Ramón y Cajal thought the size and shape of individual neurons was governed by simple rules to save cellular material and to reduce signal conduction delay. In this study, we investigated how these rules applied to whole axonal trees in neocortex by comparing their 3D structure to equivalent artificial arbors optimized for these rules. We discovered that neocortical axonal trees achieve a balance between these two rules so that a little more cellular material than necessary was used to substantially reduce conduction delays. Importantly, we suggest the nature of arbor branching balances time and material so that neocortical axons may communicate with a high degree of temporal precision, enabling accurate and rapid computation within local cortical networks. This approach could be applied to other neural structures to better understand the functional principles of brain design.
PMCID: PMC2837396  PMID: 20300651
18.  Auditory cortex of bats and primates: managing species-specific calls for social communication 
Individuals of many animal species communicate with each other using sounds or “calls” that are made up of basic acoustic patterns and their combinations. We are interested in questions about the processing of communication calls and their representation within the mammalian auditory cortex. Our studies compare in particular two species for which a large body of data has accumulated: the mustached bat and the rhesus monkey. We conclude that the brains of both species share a number of functional and organizational principles, which differ only in the extent to which and how they are implemented. For instance, neurons in both species use “combination-sensitivity” (nonlinear spectral and temporal integration of stimulus components) as a basic mechanism to enable exquisite sensitivity to and selectivity for particular call types. Whereas combination-sensitivity is already found abundantly at the primary auditory cortical and also at subcortical levels in bats, it becomes prevalent only at the level of the lateral belt in the secondary auditory cortex of monkeys. A parallel-hierarchical framework for processing complex sounds up to the level of the auditory cortex in bats and an organization into parallel-hierarchical, cortico-cortical auditory processing streams in monkeys is another common principle. Response specialization of neurons seems to be more pronounced in bats than in monkeys, whereas a functional specialization into “what” and “where” streams in the cerebral cortex is more pronounced in monkeys than in bats. These differences, in part, are due to the increased number and larger size of auditory areas in the parietal and frontal cortex in primates. Accordingly, the computational prowess of neural networks and the functional hierarchy resulting in specializations is established early and accelerated across brain regions in bats. The principles proposed here for the neural “management” of species-specific calls in bats and primates can be tested by studying the details of call processing in additional species. Also, computational modeling in conjunction with coordinated studies in bats and monkeys can help to clarify the fundamental question of perceptual invariance (or “constancy”) in call recognition, which has obvious relevance for understanding speech perception and its disorders in humans.
PMCID: PMC4276140  PMID: 17485400
Language; Speech; Neural coding; Bats; Primates; Review
19.  Comparative Anatomy of the Locus Coeruleus in Humans and Non-Human Primates 
The locus coeruleus (LC) is a dense cluster of neurons that projects axons throughout the neuroaxis and is located in the rostral pontine tegmentum extending from the level of the inferior colliculus to the motor nucleus of the trigeminal nerve. LC neurons are lost in the course of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. In this study, we used Nissl staining and tyrosine hydroxylase (TH) immunoreactivity to compare the human LC with that of closely related primate species, including great and lesser apes, and macaque monkeys. TH catalyzes the initial and rate-limiting step in catecholamine biosynthesis. The number of TH-immunoreactive (TH-ir) neurons was estimated in each species using stereologic methods. In the LC of humans, the mean total number of TH-ir neurons was significantly higher compared to the other primates. Because the total number of TH-ir neurons in the LC was highly correlated with the species mean volume of the medulla oblongata, cerebellum, and neocortical gray matter, we conclude that much of the observed phylogenetic variation can be explained by anatomical scaling. Notably, the total number of LC neurons in humans was most closely predicted by the nonhuman allometric scaling relationship relative to medulla size, whereas the number of LC neurons in humans was considerably lower than predicted according to neocortex and cerebellum volume.
PMCID: PMC2820586  PMID: 20127761
Locus coeruleus; non-human primates; hominids; tyrosine hydroxylase; stereology
20.  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
21.  Development of structural MR brain imaging protocols to study genetics and maturation 
Methods (San Diego, Calif.)  2009;50(3):136-146.
Structural imaging research offers excellent translational benefits when non-human primate (NHP) models are employed. In this paper, we will discuss the development of anatomical MR imaging protocols for two important applications of structural imaging in NHP: studies of genetic variability in brain morphology and longitudinal imaging of fetal brain maturation trends. In contrast with imaging studies of adult humans, structural imaging in the NHP is challenging due to a comparatively small brain size (2-200 fold smaller volume, depending on the species). This difference in size is further accentuated in NHP studies of brain development, in which fetal brain volumes are 10-50% of their adult size. The sizes of cortical gyri and sulci scale allometrically with brain size. Thus, achieving spatial sampling that is comparable to that of high-quality human studies (∼1.0 mm3) requires a brain-size-adjusted reduction in the sampling volumes of from 500-to-150 microns3. Imaging at this spatial resolution while maintaining sufficient contrast and signal to noise ratio necessitates the development of specialized MRI protocols. Here we discuss our strategy to optimize the protocol parameters for two commonly available structural imaging sequences: MPRAGE and TrueFisp. In addition, computational tools developed for the analysis of human structural images were applied to the NHP studies. These included removal of non-brain tissues, correction for RF inhomogeneity, spatial normalization, building of optimized target brain and analysis of cerebral gyrification and individual cortical variability. Finally, recent findings in the genetics of cerebral gyrification and tracking of maturation trends in the fetal, newborn and adult brain are described
PMCID: PMC2828529  PMID: 19665566
22.  Life-history variation and allometry for sexual size dimorphism in Pacific salmon and trout 
Allometry for sexual size dimorphism (SSD) is common in animals, but how different evolutionary processes interact to determine allometry remains unclear. Among related species SSD (male:female) typically increases with average body size, resulting in slopes of less than 1 when female size is regressed on male size: an allometric relationship formalized as ‘Rensch's rule’ . Empirical studies show that taxa with male-biased SSD are more likely to satisfy Rensch's rule and that a taxon's mean SSD is negatively correlated with allometric slope, implicating sexual selection on male size as an important mechanism promoting allometry for SSD. I use body length (and life-history) data from 628 (259) populations of seven species of anadromous Pacific salmon and trout (Oncorhynchus spp.) to show that in this genus life-history variation appears to regulate patterns of allometry both within and between species. Although all seven species have intraspecific allometric slopes of less than 1, contrary to expectation slope is unrelated to species' mean SSD, but is instead negatively correlated with two life-history variables: the species' mean marine age and variation in marine age. Second, because differences in marine age among species render SSD and body size uncorrelated, the interspecific slope is isometric. Together, these results provide an example of how evolutionary divergence in life history among related species can affect patterns of allometry for SSD across taxonomic scales.
PMCID: PMC1634950  PMID: 15695207
sexual size dimorphism; allometry; Rensch's rule; Pacific salmon and trout; life history
23.  Pyramidal cells in V1 of African rodents are bigger, more branched and more spiny than those in primates 
Pyramidal cells are characterized by markedly different sized dendritic trees, branching patterns, and spine density across the cortical mantle. Moreover, pyramidal cells have been shown to differ in structure among homologous cortical areas in different species; however, most of these studies have been conducted in primates. Whilst pyramidal cells have been quantified in a few cortical areas in some other species there are, as yet, no uniform comparative data on pyramidal cell structure in a homologous cortical area among species in different Orders. Here we studied layer III pyramidal cells in V1 of three species of rodents, the greater cane rat, highveld gerbil, and four-striped mouse, by the same methodology used to sample data from layer III pyramidal cells in primates. The data reveal markedly different trends between rodents and primates: there is an appreciable increase in the size, branching complexity, and number of spines in the dendritic trees of pyramidal cells with increasing size of V1 in the brain in rodents, whereas there is relatively little difference in primates. Moreover, pyramidal cells in rodents are larger, more branched and more spinous than those in primates. For example, the dendritic trees of pyramidal cells in V1 of the adult cane rat are nearly three times larger, and have more than 10 times the number of spines in their basal dendritic trees, than those in V1 of the adult macaque (7900 and 600, respectively), which has a V1 40 times the size that of the cane rat. It remains to be determined to what extent these differences may result from development or reflect evolutionary and/or processing specializations.
PMCID: PMC3918685  PMID: 24574977
striate; cortex; dendrite; spine; Lucifer yellow
24.  Local and Remote Growth Factor Effects After Primate Spinal Cord Injury 
Primate models of spinal cord injury differ from rodent models in several respects, including the relative size and functional neuroanatomy of spinal projections. Fundamental differences in scale raise the possibility that retrograde injury signals, and treatments applied at the level of the spinal cord that exhibit efficacy in rodents, may fail to influence neurons at the far greater distances of primate systems. Thus, we examined both local and remote neuronal responses to neurotrophic factor-secreting cell grafts placed within sites of right C7 hemisection lesions in the rhesus macaque. Six months after gene delivery of BDNF and NT-3 into C7 lesion sites, we found both local effects of growth factors on axonal growth, and remote effects of growth factors reflected in significant reductions in axotomy-induced atrophy of large pyramidal neurons within the primary motor cortex. Further examination in a rodent model suggested that BDNF, rather than NT-3, mediated remote protection of corticospinal neurons in the brain. Thus, injured neural systems retain the ability to respond to growth signals over the extended distances of the primate CNS, promoting local axonal growth and preventing lesion-induced neuronal degeneration at a distance. Remote cortical effects of spinally-administered growth factors could “prime” the neuron to respond to experimental therapies that promote axonal plasticity or regeneration.
PMCID: PMC2927098  PMID: 20660255
neurotrophic factors; spinal cord injury; non-human primate; axonal growth; motor cortex; neuroprotection
25.  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

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