The Multiple Contexts of Brain Scaling: Phenotypic Integration in Brain and Behavioral Evolution.

Understanding the adaptive functions of increasing brain size have occupied scientists for decades.  Here, taking the general perspective of the Extended Evolutionary Synthesis, the question of how brains change in size will be considered in two developmental frameworks. The first framework will consider the particular developmental mechanisms that control and generate brain mass, concentrating on neurogenesis in a comparative vertebrate context. The consequences of limited adult neurogenesis in mammals, and the dominating role of duration of neurogenesis for mammalian evolution will be discussed for the particular case of the teleost versus mammalian retina, and for paths of brain evolution more generally. The second framework examines brain mass in terms of life history, particularly the features of life history that correlate highly, if imperfectly, with brain mass, including duration of development to adolescence, duration of parental care, body and range size, and longevity. This covariation will be examined in light of current work on genetic causes and consequences of covariation in craniofacial bone groupings. The eventual development of a multivariate structure for understanding brain evolution which specifically integrates formerly separate layers of analysis is the ultimate goal.

Developmental duration as an organizer of the evolving mammalian brain: scaling, adaptations, and exceptions.

Neurodevelopmental duration plays a central role in the evolution of the retina and neocortex in mammals. In the diurnal primate eye and retina, it is necessary to scale the number of cones versus the number of rods with different exponents to defend their respective functions of spatial acuity and sensitivity in eyes of different sizes. The order of photoreceptor precursor specification, cones specified first, rods second, couples their respective cell numbers at maturity to the kinetics of embryonic stem cell proliferation. Different durations of retinogenesis change the ratio of rods to cones produced so as to defend both functions over a range of eye diameters. In the evolution of nocturnality, the same coupling of photoreceptor specification to neurogenesis is altered to fewer cones and many more rods in nocturnal eyes, by delaying the onset of retinogenesis. Similarly, the neocortex also shows coupling of the specification of laminar position with duration of neurogenesis. Overall, duration of neurogenesis directly predicts neocortex volume in most mammalian clades. In larger brains with longer neocortical neurogenesis, its organization changes progressively, differentiating the frontal pole from the occipital pole in volume of connectivity and number of neurons per unit column. This permits greater, hierarchically organized information abstraction with increasing neocortex volume. Exceptions do exist, however, in species of three separate taxa, marsupials, naked mole rats, and bats, which break the correlation of neurodevelopmental duration and brain size. Naked mole rats and bats both have small brains and unusual longevity, coupled with neurodevelopmental periods characteristic of much bigger-brained animals, raising the possibility that developmental duration and lifespan have some genetic or mechanistic control in common. The role of duration of development in mediating between the mechanistic levels of construction of retinal and cortical organization, and the different life histories associated with larger brains, such as duration of parental care, learning and overall longevity are discussed.

Principles of Network Architecture Emerging from Comparisons of the Cerebral Cortex in Large and Small Brains.

The cerebral cortex retains its fundamental organization, layering, and input-output relations as it scales in volume over many orders of magnitude in mammals. How is its network architecture affected by size scaling? By comparing network organization of the mouse and rhesus macaque cortical connectome derived from complete neuroanatomical tracing studies, a recent study in PLOS Biology shows that an exponential distance rule emerges that reveals the falloff in connection probability with distance in the two brains that in turn determines common organizational features.

Generic Homo sapiens and Unique Mus musculus: Establishing the Typicality of the Modeled and the Model Species.

The question of how complex human abilities evolved, such as language or face recognition, has been pursued by means of multiple strategies. Highly specialized non-human species have been examined analytically for formal similarities, close phylogenetic relatives have been examined for continuity, and simpler species have been analyzed for the broadest view of functional organization. All these strategies require empirical evidence of what is variable and predictable in both the modeled and the model species. Turning to humans, allometric analyses of the evolution of brain mass and brain components often return the interesting, but disappointing answer that volumetric organization of the human brain is highly predictable seen in its phylogenetic context. Reconciling this insight with unique human behavior, or any species-typical behavior, represents a serious challenge. Allometric analyses of the order and duration of mammalian neural development show that, while basic neural development in humans is allometrically predictable, conforming to adult neural architecture, some life history features deviate, notably that weaning is unusually early. Finally, unusual deviations in the retina and central auditory system in the laboratory mouse, which is widely assumed to be "generic," as well as severe deviations from expected brain allometry in some mouse strains, underline the need for a deeper understanding of phylogenetic variability even in those systems believed to be best understood.

Human exceptionalism, our ordinary cortex and our research futures.

The widely held belief that the human cortex is exceptionally large for our brain size is wrong, resulting from basic errors in how best to compare evolving brains. This misapprehension arises from the comparison of only a few laboratory species, failure to appreciate differences in brain scaling in rodents versus primates, but most important, the false assumption that linear extrapolation can be used to predict changes from small to large brains. Belief in the exceptionalism of human cortex has propagated itself into genomic analysis of the cortex, where cortex has been studied as if it were an example of innovation rather than predictable scaling. Further, this belief has caused both neuroscientists and psychologists to prematurely assign functions distributed widely in the brain to the cortex, to fail to explore subcortical sources of brain evolution, and to neglect genuinely novel features of human infancy and childhood.

Coevolution in the timing of GABAergic and pyramidal neuron maturation in primates.

The cortex of primates is relatively expanded compared with many other mammals, yet little is known about what developmental processes account for the expansion of cortical subtype numbers in primates, including humans. We asked whether GABAergic and pyramidal neuron production occurs for longer than expected in primates than in mice in a sample of 86 developing primate and rodent brains. We use high-resolution structural, diffusion MR scans and histological material to compare the timing of the ganglionic eminences (GE) and cortical proliferative pool (CPP) maturation between humans, macaques, rats, and mice. We also compare the timing of post-neurogenetic maturation of GABAergic and pyramidal neurons in primates (i.e. humans, macaques) relative to rats and mice to identify whether delays in neurogenesis are concomitant with delayed post-neurogenetic maturation. We found that the growth of the GE and CPP are both selectively delayed compared with other events in primates. By contrast, the timing of post-neurogenetic GABAergic and pyramidal events (e.g. synaptogenesis) are predictable from the timing of other events in primates and in studied rodents. The extended duration of GABAergic and pyramidal neuron production is associated with the amplification of GABAerigc and pyramidal neuron numbers in the human and non-human primate cortex.

Modeling local and cross-species neuron number variations in the cerebral cortex as arising from a common mechanism.

A massive increase in the number of neurons in the cerebral cortex, driving its size to increase by five orders of magnitude, is a key feature of mammalian evolution. Not only are there systematic variations in cerebral cortical architecture across species, but also across spatial axes within a given cortex. In this article we present a computational model that accounts for both types of variation as arising from the same developmental mechanism. The model employs empirically measured parameters from over a dozen species to demonstrate that changes to the kinetics of neurogenesis (the cell-cycle rate, the progenitor death rate, and the "quit rate," i.e., the ratio of terminal cell divisions) are sufficient to explain the great diversity in the number of cortical neurons across mammals. Moreover, spatiotemporal gradients in those same parameters in the embryonic cortex can account for cortex-wide, graded variations in the mature neural architecture. Consistent with emerging anatomical data in several species, the model predicts (i) a greater complement of neurons per cortical column in the later-developing, posterior regions of intermediate and large cortices, (ii) that the extent of variation across a cortex increases with cortex size, reaching fivefold or greater in primates, and (iii) that when the number of neurons per cortical column increases, whether across species or within a given cortex, it is the later-developing superficial layers of the cortex which accommodate those additional neurons. We posit that these graded features of the cortex have computational and functional significance, and so must be subject to evolutionary selection.

Systematic, cross-cortex variation in neuron numbers in rodents and primates.

Uniformity, local variability, and systematic variation in neuron numbers per unit of cortical surface area across species and cortical areas have been claimed to characterize the isocortex. Resolving these claims has been difficult, because species, techniques, and cortical areas vary across studies. We present a stereological assessment of neuron numbers in layers II-IV and V-VI per unit of cortical surface area across the isocortex in rodents (hamster, Mesocricetus auratus; agouti, Dasyprocta azarae; paca, Cuniculus paca) and primates (owl monkey, Aotus trivigratus; tamarin, Saguinus midas; capuchin, Cebus apella); these chosen to vary systematically in cortical size. The contributions of species, cortical areas, and techniques (stereology, "isotropic fractionator") to neuron estimates were assessed. Neurons per unit of cortical surface area increase across the rostro-caudal (RC) axis in primates (varying by a factor of 1.64-2.13 across the rostral and caudal poles) but less in rodents (varying by a factor of 1.15-1.54). Layer II-IV neurons account for most of this variation. When integrated into the context of species variation, and this RC gradient in neuron numbers, conflicts between studies can be accounted for. The RC variation in isocortical neurons in adulthood mirrors the gradients in neurogenesis duration in development.

Modeling transformations of neurodevelopmental sequences across mammalian species.

A general model of neural development is derived to fit 18 mammalian species, including humans, macaques, several rodent species, and six metatherian (marsupial) mammals. The goal of this work is to describe heterochronic changes in brain evolution within its basic developmental allometry, and provide an empirical basis to recognize equivalent maturational states across animals. The empirical data generating the model comprises 271 developmental events, including measures of initial neurogenesis, axon extension, establishment, and refinement of connectivity, as well as later events such as myelin formation, growth of brain volume, and early behavioral milestones, to the third year of human postnatal life. The progress of neural events across species is sufficiently predictable that a single model can be used to predict the timing of all events in all species, with a correlation of modeled values to empirical data of 0.9929. Each species' rate of progress through the event scale, described by a regression equation predicting duration of development in days, is highly correlated with adult brain size. Neural heterochrony can be seen in selective delay of retinogenesis in the cat, associated with greater numbers of rods in its retina, and delay of corticogenesis in all species but rodents and the rabbit, associated with relatively larger cortices in species with delay. Unexpectedly, precocial mammals (those unusually mature at birth) delay the onset of first neurogenesis but then progress rapidly through remaining developmental events.

Evo-devo and the primate isocortex: the central organizing role of intrinsic gradients of neurogenesis.

Spatial gradients in the initiation and termination of basic processes, such as cytogenesis, cell-type specification and dendritic maturation, are ubiquitous in developing nervous systems. Such gradients can produce a niche adaptation in a particular species. For example, the high density of photoreceptors and neurons in the 'area centralis' of some vertebrate retinas result from the early maturation of its center relative to its periphery. Across species, regularities in allometric scaling of brain regions can derive from conserved spatial gradients: longer neurogenesis in the alar versus the basal plate of the neural tube is associated with relatively greater expansion of alar plate derivatives in larger brains. We describe gradients of neurogenesis within the isocortex and their effects on adult cytoarchitecture within and across species. Longer duration of neurogenesis in the caudal isocortex is associated with increased neuron number and density per column relative to the rostral isocortex. Later-maturing features of single neurons, such as soma size and dendritic spine numbers reflect this gradient. Considering rodents and primates, the longer the duration of isocortical neurogenesis in each species, the greater the rostral-to-caudal difference in neuron number and density per column. Extended developmental duration produces substantial, predictable changes in the architecture of the isocortex in larger brains, and presumably a progressively changed functional organization, the properties of which we do not yet fully understand. Many features of isocortical architecture previously viewed as species- or niche-specific adaptations can now be integrated as the natural outcomes of spatiotemporal gradients that are deployed in larger brains.

NSF workshop report: discovering general principles of nervous system organization by comparing brain maps across species.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.

Variation in human brains may facilitate evolutionary change toward a limited range of phenotypes.

Individual variation is the foundation for evolutionary change, but little is known about the nature of normal variation between brains. Phylogenetic variation across mammalian brains is characterized by high intercorrelations in brain region volumes, distinct allometric scaling for each brain region and the relative independence of olfactory and limbic structure volumes from the rest of the brain. Previous work examining brain variation in individuals of some domesticated species showed that these three features of phylogenetic variation were mirrored in individual variation. We extend this analysis to the human brain and 10 of its subdivisions (e.g., isocortex and hippocampus) by using magnetic resonance imaging scans of 90 human brains ranging between 16 and 25 years of age. Human brain variation resembles both the individual variation seen in other species and variation observed across mammalian species, i.e., the relative differences in the slopes of each brain region compared to medulla size within humans and between mammals are concordant, and limbic structures scale with relative independence from other brain regions. This nonrandom pattern of variation suggests that developmental programs channel the variation available for selection.

A conserved pattern of brain scaling from sharks to primates.

Several patterns of brain allometry previously observed in mammals have been found to hold for sharks and related taxa (chondrichthyans) as well. In each clade, the relative size of brain parts, with the notable exception of the olfactory bulbs, is highly predictable from the total brain size. Compared with total brain mass, each part scales with a characteristic slope, which is highest for the telencephalon and cerebellum. In addition, cerebellar foliation reflects both absolute and relative cerebellar size, in a manner analogous to mammalian cortical gyrification. This conserved pattern of brain scaling suggests that the fundamental brain plan that evolved in early vertebrates permits appropriate scaling in response to a range of factors, including phylogeny and ecology, where neural mass may be added and subtracted without compromising basic function.

Developmental sources of conservation and variation in the evolution of the primate eye.

Conserved developmental programs, such as the order of neurogenesis in the mammalian eye, suggest the presence of useful features for evolutionary stability and variability. The owl monkey, Aotus azarae, has developed a fully nocturnal retina in recent evolution. Description and quantification of cell cycle kinetics show that embryonic cytogenesis is extended in Aotus compared with the diurnal New World monkey Cebus apella. Combined with the conserved mammalian pattern of retinal cell specification, this single change in retinal progenitor cell proliferation can produce the multiple alterations of the nocturnal retina, including coordinated reduction in cone and ganglion cell numbers, increase in rod and rod bipolar numbers, and potentially loss of the fovea.

The neuroecology of the water-to-land transition and the evolution of the vertebrate brain.

The water-to-land transition in vertebrate evolution offers an unusual opportunity to consider computational affordances of a new ecology for the brain. All sensory modalities are changed, particularly a greatly enlarged visual sensorium owing to air versus water as a medium, and expanded by mobile eyes and neck. The multiplication of limbs, as evolved to exploit aspects of life on land, is a comparable computational challenge. As the total mass of living organisms on land is a hundredfold larger than the mass underwater, computational improvements promise great rewards. In water, the midbrain tectum coordinates approach/avoid decisions, contextualized by water flow and by the animal's body state and learning. On land, the relative motions of sensory surfaces and effectors must be resolved, adding on computational architectures from the dorsal pallium, such as the parietal cortex. For the large-brained and long-living denizens of land, making the right decision when the wrong one means death may be the basis of planning, which allows animals to learn from hypothetical experience before enactment. Integration of value-weighted, memorized panoramas in basal ganglia/frontal cortex circuitry, with allocentric cognitive maps of the hippocampus and its associated cortices becomes a cognitive habit-to-plan transition as substantial as the change in ecology. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Thinking outside the cortex: social motivation in the evolution and development of language.

Alteration of the organization of social and motivational neuroanatomical circuitry must have been an essential step in the evolution of human language. Development of vocal communication across species, particularly birdsong, and new research on the neural organization and evolution of social and motivational circuitry, together suggest that human language is the result of an obligatory link of a powerful cortico-striatal learning system, and subcortical socio-motivational circuitry.

Evo-devo and brain scaling: candidate developmental mechanisms for variation and constancy in vertebrate brain evolution.

Biologists have long been interested in both the regularities and the deviations in the relationship between brain, development, ecology, and behavior between taxa. We first examine some basic information about the observed ranges of fundamental changes in developmental parameters (i.e. neurogenesis timing, cell cycle rates, and gene expression patterns) between taxa. Next, we review what is known about the relative importance of different kinds of developmental mechanisms in producing brain change, focusing on mechanisms of segmentation, local and general features of neurogenesis, and cell cycle kinetics. We suggest that a limited set of developmental alterations of the vertebrate nervous system typically occur and that each kind of developmental change may entail unique anatomical, functional, and behavioral consequences for the organism. Thus, neuroecologists who posit a direct mapping of brain size to behavior should consider that not any change in brain anatomy is possible.

Rod bipolar cells in the retina of the capuchin monkey (Cebus apella): characterization and distribution.

Rod bipolar cells in Cebus apella monkey retina were identified by an antibody against the alpha isoform of protein kinase C (PKCalpha), which has been shown to selectively identify rod bipolars in two other primates and various mammals. Vertical sections were used to confirm the identity of these cells by their characteristic morphology of dendrites and axons. Their topographic distribution was assessed in horizontal sections; counts taken along the dorsal, ventral, nasal, and temporal quadrants. The density of rod bipolar cells increased from 500 to 2900 cells/mm2 at 1 mm from the fovea to reach a peak of 10,000-12,000 cells/mm2 at 4 mm, approximately 5 deg of eccentricity, and then gradually decreased toward retinal periphery to values of 5000 cells/mm2 or less. Rod to rod bipolar density ratio remained between 10 and 20 across most of the retinal extension. The number of rod bipolar cells per retina was 6,360,000 +/- 387,433 (mean +/- s.d., n = 6). The anti-PKCalpha antibody has shown to be a good marker of rod bipolar cells of Cebus, and the cell distribution is similar to that described for other primates. In spite of the difference in the central retina, the density variation of rod bipolar cells in the Cebus and Macaca as well as the convergence from rod to rod bipolar cells are generally similar, suggesting that both retinae stabilize similar sensitivity (as measured by rod density) and convergence.

The neuroscience of vision and pain: evolution of two disciplines.

Research in the neuroscience of pain perception and visual perception has taken contrasting paths. The contextual and the social aspects of pain judgements predisposed pain researchers to develop computational and functional accounts early, while vision researchers tended to simple localizationist or descriptive approaches first. Evolutionary thought was applied to distinct domains, such as game-theoretic approaches to cheater detection in pain research, versus vision scientists' studies of comparative visual ecologies. Both fields now contemplate current motor or decision-based accounts of perception, particularly predictive coding. Vision researchers do so without the benefit of earlier attention to social and motivational aspects of vision, while pain researchers lack a comparative behavioural ecology of pain, the normal incidence and utility of responses to tissue damage. Hybrid hypotheses arising from predictive coding as used in both domains are applied to some perplexing phenomena in pain perception to suggest future directions. The contingent and predictive interpretation of complex sensations, in such domains as 'runner's high', multiple cosmetic procedures, self-harm and circadian rhythms in pain sensitivity is one example. The second, in an evolutionary time frame, considers enhancement of primary perception and expression of pain in social species, when expressions of pain might reliably elicit useful help. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

The developing and evolving retina: using time to organize form.

Evolutionary and other functional accounts of the retina and its normal development highlight different aspects of control of its growth and form than genomic and mechanistic accounts. Discussing examples from opsin expression, developmental regulation of the eye's size and optical quality, regulation of eye size with respect to brain and body size, and the development of the fovea, these different aspects of control are contrasted. Contributions of mouse models, particularly with regard to relative timing of events in different species are reviewed, introducing a Web-based utility for exploration of timing issues (www.translatingtime.net). Variation at the individual level, in early experience, and also across species is an essential source of information to understand normal development and its pathologies.