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Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional | Manger P.R.,University of Witwatersrand | Kaas J.H.,Vanderbilt University
Frontiers in Neuroanatomy | Year: 2014

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. © 2014 Herculano-Houzel, Manger and Kaas.

Mortera P.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
Frontiers in Neuroanatomy | Year: 2012

Aging-related changes in the brain have been mostly studied through the comparison of young adult and very old animals. However, aging must be considered a lifelong process of cumulative changes that ultimately become evident at old age. To determine when this process of decline begins, we studied how the cellular composition of the rat brain changes from infancy to adolescence, early adulthood, and old age. Using the isotropic fractionator to determine total numbers of neuronal and non-neuronal cells in different brain areas, we find that a major increase in number of neurons occurs during adolescence, between 1 and 2-3 months of age, followed by a significant trend of widespread and progressive neuronal loss that begins as early as 3 months of age, when neuronal numbers are maximal in all structures, until decreases in numbers of neurons become evident at 12 or 22 months of age. Our findings indicate that age-related decline in the brain begins as soon as the end of adolescence, a novel finding has important clinical and social implications for public health and welfare. © 2012 Morterá and Herculano-houzel.

Mota B.,Federal University of Rio de Janeiro | Mota B.,Instituto Nacional Of Neurociencia Translacional | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional | Herculano-Houzel S.,Federal University of Rio de Janeiro
Frontiers in Neuroanatomy | Year: 2014

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. © 2014 Mota and Herculano-Houzel.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
GLIA | Year: 2014

It is a widespread notion that the proportion of glial to neuronal cells in the brain increases with brain size, to the point that glial cells represent "about 90% of all cells in the human brain." This notion, however, is wrong on both counts: neither does the glia/neuron ratio increase uniformly with brain size, nor do glial cells represent the majority of cells in the human brain. This review examines the origin of interest in the glia/neuron ratio; the original evidence that led to the notion that it increases with brain size; the extent to which this concept can be applied to white matter and whole brains and the recent supporting evidence that the glia/neuron ratio does not increase with brain size, but rather, and in surprisingly uniform fashion, with decreasing neuronal density due to increasing average neuronal cell size, across brain structures and species. Variations in the glia/neuron ratio are proposed to be related not to the supposed larger metabolic cost of larger neurons (given that this cost is not found to vary with neuronal density), but simply to the large variation in neuronal sizes across brain structures and species in the face of less overall variation in glial cell sizes, with interesting implications for brain physiology. The emerging evidence that the glia/neuron ratio varies uniformly across the different brain structures of mammalian species that diverged as early as 90 million years ago in evolution highlights how fundamental for brain function must be the interaction between glial cells and neurons. © 2014 Wiley Periodicals, Inc.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional | von Bartheld C.S.,University of Nevada, Reno | Miller D.J.,Vanderbilt University | Kaas J.H.,Vanderbilt University
Cell and Tissue Research | Year: 2015

The number of cells comprising biological structures represents fundamental information in basic anatomy, development, aging, drug tests, pathology and genetic manipulations. Obtaining unbiased estimates of cell numbers, however, was until recently possible only through stereological techniques, which require specific training, equipment, histological processing and appropriate sampling strategies applied to structures with a homogeneous distribution of cell bodies. An alternative, the isotropic fractionator (IF), became available in 2005 as a fast and inexpensive method that requires little training, no specific software and only a few materials before it can be used to quantify total numbers of neuronal and non-neuronal cells in a whole organ such as the brain or any dissectible regions thereof. This method entails transforming a highly anisotropic tissue into a homogeneous suspension of free-floating nuclei that can then be counted under the microscope or by flow cytometry and identified morphologically and immunocytochemically as neuronal or non-neuronal. We compare the advantages and disadvantages of each method and provide researchers with guidelines for choosing the best method for their particular needs. IF is as accurate as unbiased stereology and faster than stereological techniques, as it requires no elaborate histological processing or sampling paradigms, providing reliable estimates in a few days rather than many weeks. Tissue shrinkage is also not an issue, since the estimates provided are independent of tissue volume. The main disadvantage of IF, however, is that it necessarily destroys the tissue analyzed and thus provides no spatial information on the cellular composition of biological regions of interest. © 2015, Springer-Verlag Berlin Heidelberg.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
Annals of the New York Academy of Sciences | Year: 2011

It is usually considered a paradox that the human brain, although smaller than elephant and cetacean brains, is the most cognitively able. The concept that humans are more encephalized than all other mammals appeared in the 1970s as a solution to that paradox: humans have a brain that is much larger than expected from their body mass. Such an "excess brain mass" would provide increased cognitive abilities across species, thus explaining our cognitive superiority. However, behind the paradox lies the assumption that large mammalian brains are scaled-up versions of smaller brains, always containing more neurons than smaller ones-an assumption that we have recently shown to be invalid. Here, it is proposed that the absolute number of neurons, irrespective of brain or body size, is a better predictor of cognitive ability-in which case, the cognitive superiority of humans would come as no paradox, surprise, or exception to evolutionary rules. © 2011 New York Academy of Sciences.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
PLoS ONE | Year: 2011

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. © 2011 Suzana Herculano-Houzel.

Mota B.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
Science | Year: 2015

Larger brains tend to have more folded cortices, but what makes the cortex fold has remained unknown. We show that the degree of cortical folding scales uniformly across lissencephalic and gyrencephalic species, across individuals, and within individual cortices as a function of the product of cortical surface area and the square root of cortical thickness. This relation is derived from the minimization of the effective free energy associated with cortical shape according to a simple physical model, based on known mechanisms of axonal elongation. This model also explains the scaling of the folding index of crumpled paper balls. We discuss the implications of this finding for the evolutionary and developmental origin of folding, including the newfound continuum between lissencephaly and gyrencephaly, and for pathologies such as human lissencephaly. © 2015, American Association for the Advancement of Science. All rights reserved.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
Neuromethods | Year: 2012

Stereological techniques that estimate cell numbers require specific training and elaborate sampling strategies to infer total numbers of cells in well-defined structures of measurable volume. The isotropic fractionator is a fast and inexpensive method that requires little specific training and few materials before it can be used to quantify total numbers of neuronal and nonneuronal cells in the whole brain or any dissectible regions thereof. It consists in transforming highly anisotropic (paraformaldehyde fixed and dissected) brain structures into homogeneous, isotropic suspensions of cell nuclei which can be counted and identified morphologically and immunocytochemically as neuronal or nonneuronal. Estimates of total cell, neuronal and nonneuronal, numbers can be obtained within 24 h, and vary by less than 10% among samples of the same structure. Since the estimates obtained are independent of brain volume, they can be used in comparative studies of brain volume variation among species and in studies of phylogenesis, development, adult neurogenesis, and pathology. © 2011 Springer Science+Business Media, LLC.

Herculano-Houzel S.,Federal University of Rio de Janeiro | Herculano-Houzel S.,Instituto Nacional Of Neurociencia Translacional
Proceedings of the Royal Society B: Biological Sciences | Year: 2015

Mammals sleep between 3 and 20 h d-1, but what regulates daily sleep requirement is unknown. While mammalian evolution has been characterized by a tendency towards larger bodies and brains, sustaining larger bodies and brains requires increasing hours of feeding per day, which is incompatible with a large sleep requirement. Mammalian evolution, therefore, must involve mechanisms that tie increasing body and brain size to decreasing sleep requirements. Here I show that daily sleep requirement decreases across mammalian species and in rat postnatal development with a decreasing ratio between cortical neuronal density and surface area, which presumably causes sleep-inducing metabolites to accumulate more slowly in the parenchyma. Because addition of neurons to the non-primate cortex in mammalian evolution decreases this ratio, I propose that increasing numbers of cortical neurons led to decreased sleep requirement in evolution that allowed for more hours of feeding and increased body mass, which would then facilitate further increases in numbers of brain neurons through a larger caloric intake per hour. Coupling of increasing numbers of neurons to decreasing sleep requirement and increasing hours of feeding thus may have not only allowed but also driven the trend of increasing brain and body mass in mammalian evolution. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

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