Biology subjects

Herculano-Houzel, S.

Publications and source records attributed to Herculano-Houzel, S..

9 recordsLinked to original sources

bioRxiv2025

Home range is not constrained by number of hippocampal neurons across mammals

Numbers of hippocampal neurons vary by over three orders of magnitude across mammalian species. What evolutionary pressures shape this diversity? Given the role of the hippocampus in spatial mapping, the greater spatial navigation demands of larger home ranges may drive selection for more hippocampal neuron. Using data from 379 species, we crossed home range and population density data with cortical and hippocampal neuron counts predicted from clade-specific brain scaling laws to examine whether home range scales universally with estimated hippocampal neuron numbers across mammals. We confirm that home range scales universally with the inverse of population density across species and increases with body mass and metabolic rate. However, home range scaling with hippocampal or cortical neuron numbers differs by clade, such that bats, carnivorans and cetartiodactyls traverse home ranges over 1,000-fold larger than other mammals with equivalent hippocampal neuron numbers. These findings persist across data subsets controlling for study method, duration, and temporal scope. Numbers of hippocampal neurons are thus not limiting to spatial navigation in the wild, calling into question adaptationist explanations for the evolution of more hippocampal neurons based on a supposed need for increased spatial processing capacity. We propose that home range is determined primarily by population density, mediated by field metabolic rate and diet. The diversity in hippocampal neuron numbers across mammals, in turn, arises as a byproduct of clade-specific scaling of numbers of cortical neurons which we suggest is contingent on energetic opportunity, not on navigational or other cognitive demands. Significance StatementWhy do some animals have so many more brain neurons than others? One explanation is evolution through selection for more neurons as needed for instance to navigate their environments to find food. However, this study finds that bats, carnivorans and whales traverse distances more than 1,000-fold larger than other mammals with similar numbers of neurons in the hippocampus, the brain structure required for spatial navigation. The authors question the traditional need-based explanation for brain diversity in favor of an opportunity-based account of the evolution of numbers of brain neurons.

neuroscience↗

bioRxiv2025

Cell Density and mRNA Expression of Inhibitory Interneurons in Schizophrenia: A Meta-Analysis

Introduction GABAergic interneurons are implicated in the pathophysiology of schizophrenia, yet evidence regarding the nature of deficits across brain areas and interneuron subtypes remains conflicting. We adopted a meta-analytic, multi-level linear modeling approach to identify interneurons, cortical layers, and brain areas involved, and the implications for circuit functions in schizophrenia. Methods Following PRISMA guidelines, we conducted a systematic search and meta-analysis from inception to November 2025, for studies examining parvalbumin, somatostatin, calbindin, and calretinin interneuron density or mRNA expression in schizophrenia. We included data from 44 studies, comprising 736 individuals with schizophrenia and 814 healthy controls. Non-cell-specific, non-human, or indirect proxy studies were excluded. Linear mixed-effects models quantified deficits while accounting for cortical layer, cell-type, and brain area, providing a map of interneuron pathology. We further analyzed changes in GABAergic interneurons to determine whether deficits preferentially target cortical layers, cell-types, and brain areas more associated with top-down or bottom-up processing. Results Parvalbumin and somatostatin interneurons showed robust reductions, particularly in layers 3/4, whilst calbindin and calretinin interneurons were less affected. Deficits were widespread across cortical and subcortical regions. Contrasts revealed that schizophrenia is characterized by interneuron deficits preferentially affecting bottom-up signaling -- notably parvalbumin and somatostatin interneurons in layers 3/4, which are critical for gamma-band synchronization and feedforward sensory processing. Discussion These findings provide the most comprehensive meta-analysis on GABAergic interneurons in schizophrenia to-date, as well as a novel perspective on circuit dysfunctions, with implications for computational models. These results highlight the need for more widespread sampling across the brain using methodologies that can pinpoint deficits in molecularly more precise ways.

neuroscience↗

bioRxiv2023

Folding of the cerebellar cortex is clade-specific in form, but universal in degree

Like the cerebral cortex, the surface of the cerebellum is repeatedly folded. Unlike the cerebral cortex, however, cerebellar folds in a given brain are much thinner and more numerous; repeat themselves largely along a single direction, forming long strips transverse to the mid-sagittal plane, like an accordion; and occur in the smallest of cerebella, including those of lissencephalic mammals and non-mammal vertebrates. We have shown previously that while the location of folds in mammalian cerebral cortex is clade-specific, the overall degree of folding strictly follows a universal power law relating cortical thickness, and the exposed and total surface areas. This law is derived from a statistical-physics model for gyrification that postulates that folding results from the interplay between axonal elongation dynamics and the self-avoiding nature of the expanding cortical surfaces. Since both aspects are present in the cerebellum, we hypothesize that a similar relation across species also exists therein. Furthermore, given the modular organization of cerebellar architecture and circuitry, as well as the transverse orientation of the folia, it is plausible that this relation is reflected in the degree of folding of the mid-sagittal section of the cerebellum, which greatly facilitates analysis. Here we show that a strict universal scaling law does apply to the folding of the mid-sagittal sections of the cerebellum of 53 species belonging to six mammalian clades, spanning a large range of sizes and degrees of gyrification. This folding is hierarchical and can be explicitly separated into branching orders, such that position of the 1st-order folds is largely stereotypical across all mammals examined. Subsequent nth-order folds become progressively less stereotypical, and folding within such cerebellar subsections scales with power laws whose exponents decrease monotonically with branching order, converging to the exponents predicted by a two-dimensional version of the same gyrification model that describes cortical folding. We propose that the changes in scaling exponent with branching order occurs as increasing amounts of white matter are included in the folding volume of the cerebellum, reflecting the difference between the outside-in development of the cerebellar cortex around a preexisting core of already connected white matter, compared to the inside-out development of the cerebral cortex with a white matter volume that develops as the cerebral cortex itself gains neurons. Our data strongly indicate that the mammalian cerebellum folds as a multi-fractal object, emerging from the interplay between clade-specificity and universality, and between phylogenetical contingency and the physics of self-organization. Thus, repeated folding, one of the most recognizable features of biology, can arise simply from the universal applicability of physical principles, without the need for invoking selective pressures in evolution; and diversity arises within the constraints imposed by physics.

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bioRxiv2022

Theropod dinosaurs had primate-like numbers of telencephalic neurons

Understanding the neuronal composition of the brains of dinosaurs and other fossil amniotes would offer fundamental insight into their behavioral and cognitive capabilities, but brain tissue is only rarely fossilized. However, when the bony brain case is preserved, the volume and therefore mass of the brain can be estimated with computer tomography; and if the scaling relationship between brain mass and numbers of neurons for the clade is known, that relationship can be applied to estimate the neuronal composition of the brain. Using a recently published database of numbers of neurons in the telencephalon of extant sauropsids (birds, squamates and testudines), here I show that the neuronal scaling rules that apply to these animals can be used to infer the numbers of neurons that composed the telencephalon of dinosaur, pterosaur and other fossil sauropsid species. The key to inferring numbers of telencephalic neurons in these species is first using the relationship between their estimated brain and body mass to determine whether bird-like (endothermic) or squamate-like (ectothermic) rules apply to each fossil sauropsid species. This procedure shows that the notion of "mesothermy" in dinosaurs is an artifact due to the mixing of animals with bird-like and squamate-like scaling, and indicates that theropods such as Tyrannosaurus and Allosaurus were endotherms with baboon- and monkey-like numbers of telencephalic neurons, respectively, which would make these animals not only giant but also long-lived and endowed with flexible cognition, and thus even more magnificent predators than previously thought.

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bioRxiv2022

Mammals, birds and non-avian reptiles have signature proportions of numbers of neurons across their brain structures: Numbers of neurons increased differently with endothermy in birds and mammals

Modern mammals, birds, and "reptiles" (squamates, turtles and crocodiles) share their developmental and evolutionary origins in the ancestral, stem amniotes of 300 million years ago. This study explores how the brains of amniotes diverged in their neuronal composition. The systematic analysis of a large dataset on the cellular composition of the major parts of the brain of 242 amniote species shows that it is not the case that a general theme in amniote evolution is the proportional expansion of the telencephalon or pallium, for such expansion only happened in owls, in primates, and in the largest mammalian species. Instead, the brains of extant mammalian, avian, and reptile species are characterized by signature proportions of numbers of neurons across the brain divisions. Reptile brains, with few exceptions, are characterized by having fewer than 10 million neurons in each brain division, with about 1.5 neurons in the telencephalon and 0.5 neuron in the cerebellum to every neuron in the rest of brain. In contrast, the brains of the closely related birds are characterized by much larger numbers of neurons that occur at a higher, fixed proportion of 4.5 neurons in the cerebellum to every neuron in the rest of brain, with variable ratios of pallial neurons. The brains of mammalian species, in turn, are characterized by larger numbers of neurons that occur at an average 4 neurons in the cerebellum to every neuron in the pallium regardless of numbers of neurons in the rest of brain. There is a striking continuity in the scaling of the pallium (or telencephalon) of extant mammalian and squamate brains that argues for a quantitative continuum between the two groups and dispels the mistaken notion that mammalian brains evolved with a qualitative change or an "addition" of structures to the "reptilian brain". The shared scaling rules between mammalian and squamate brain structures also allow for predicting the composition of early synapsid brains in amniote evolution.

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bioRxiv2021

Neuron-specific coding sequences are the most highly conserved in the mammalian brain

Neurons are unique in that they are the only cell type in the body to display massive diversity in cell size, morphology, phenotype, and function both within individuals and across species. Here we use datasets encompassing up to 92 mammalian and 31 sauropsidian species to examine whether neuron-specific diversity occurs with higher evolutionary variation of neuron-specific coding and regulatory sequences compared to non-neuronal cell-specific sequences. We find that the opposite is true: Neuronal diversity in mammalian and sauropsidian evolution arose despite extreme levels of negative selection on neuron-specific protein-coding sequences on par with ATPase coding sequences, the benchmark of evolutionary conservation. We propose that such strong evolutionary conservation is imposed by excitability, which continually exposes cells to the risk of excitotoxic death, and speculate that neuronal cell size diversity is a self-organized consequence of variability in levels of activity, possibly constrained by energy supply to the developing brain.

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bioRxiv2020

Amplification of potential thermogenetic mechanisms in cetacean brains

To elucidate causality underlying the evolution of large brains in cetaceans, we examined the brains of 16 cetartiodactyl species for evidence of non-shivering thermogenesis. In comparison to the artiodactyl brain, the cetacean brain exhibits an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, localization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.

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bioRxiv2020

Energy supply per neuron is constrained by capillary density in the mouse brain

Neuronal densities vary enormously across sites within a brain. Does the density of the capillary bed accompany the presumably larger energy requirement of sites with more neurons, or with larger neurons, or is energy supply constrained by a mostly homogeneous capillary bed? Here we find evidence for the latter across various sites in the mouse brain and show that as a result, the ratio of capillary cells per neuron, and thus presumably blood and energy supply per neuron, decreases uniformly with increasing neuronal density and therefore smaller average neuronal size across sites. Additionally, we find that local capillary density is also not correlated with local synapse densities, although there is a small but significant correlation between lower neuronal density (and therefore larger neuronal size) and more synapses per neuron within the restricted range of 6,500-9,500 across cortical sites. Further, local variations in the glial/neuron ratio are also not correlated with local variations in number of synapses per neuron or local synaptic densities. These findings suggest that it is not that larger neurons, neurons with more synapses, or even sites with more synapses demand more energy, but simply that larger (and thus fewer) neurons have more energy available per cell, and to its synapses as a whole, than smaller (and thus more numerous) neurons due to competition for limited resources supplied by a capillary bed of fairly homogeneous density throughout the brain. Significance StatementThe brain is an expensive organ and at rest already uses nearly as much energy as during sensory activation. To ultimately determine whether the high energy cost of the brain is driven by an unusually high energy demand by neurons or constrained by capillary density in the organ, we examine whether sites in the mouse brain with more neurons, larger neurons, or more synapses have more capillary supply, and find instead that capillary density is mostly homogeneous across brain structures. We propose that neurons are constrained to using what energy is available, with little evidence for adjustments according to local demand, which explains its high risk of ischemia and vulnerability to states of compromised metabolism, including normal aging.

neuroscience↗

bioRxiv2018

Lack of correlation between number of neurons and behavioral performance in Swiss mice

Neuronal number varies by several orders of magnitude across species, and has been proposed to predict cognitive capability across species. Remarkably, numbers of neurons vary across individual mice by a factor of 2 or more. We directly addressed the question of whether there is a relationship between performance in behavioral tests and the number of neurons in functionally relevant structures in the mouse brain. Naive Swiss mice went through a battery of behavioral tasks designed to measure cognitive, motor and olfactory skills. We estimated the number of neurons in different brain regions (cerebral cortex, hippocampus, olfactory bulb, cerebellum and remaining areas) and crossed the two datasets to test the a priori hypothesis of correlation between cognitive abilities and numbers of neurons. As previous evidence indicates that environmental enrichment may increase neurogenesis and improve neuronal survival, we added a control group that did not undergo cognitive testing to rule out the possibility that our test battery could alter the neuronal number. We found that behavioral testing did not change numbers of neurons in the cerebral cortex and in the hippocampus. Surprisingly, performance in the behavioral tasks did not correlate strongly with number of neurons in any of the brain regions studied. Our results show that whereas neuronal number is a good predictor of cognitive skills across species, it is not a predictor of cognitive, sensory or motor ability across individuals within a species, which suggests that other factors are more relevant for explaining cognitive differences between individuals of the same species.

neuroscience↗