Cellular scaling rules for the brains of an extended number of primate species

What are the rules relating the size of the brain and its structures to the number of cells that compose them and their average sizes? We have shown previously that the cerebral cortex, cerebellum and the remaining brain structures increase in size as a linear function of their numbers of neurons and non-neuronal cells across 6 species of primates. Here we describe that the cellular composition of the same brain structures of 5 other primate species, as well as humans, conform to the scaling rules identified previously, and that the updated power functions for the extended sample are similar to those determined earlier. Accounting for phylogenetic relatedness in the combined dataset does not affect the scaling slopes that apply to the cerebral cortex and cerebellum, but alters the slope for the remaining brain structures to a value that is similar to that observed in rodents, which raises the possibility that the neuronal scaling rules for these structures are shared among rodents and primates. The conformity of the new set of primate species to the previous rules strongly suggests that the cellular scaling rules we have identified apply to primates in general, including humans, and not only to particular subgroups of primate species. In contrast, the allometric rules relating body and brain size are highly sensitive to the particular species sampled, suggesting that brain size is neither determined by body size nor together with it, but is rather only loosely correlated with body size.     

Cellular scaling rules for primate spinal cords

The spinal cord can be considered a major sensorimotor interface between the body and the brain. How does the spinal cord scale with body and brain mass, and how are its numbers of neurons related to the number of neurons in the brain across species of different body and brain sizes? Here we determine the cellular composition of the spinal cord in eight primate species and find that its number of neurons varies as a linear function of cord length, and accompanies body mass raised to an exponent close to 1/3. This relationship suggests that the extension, mass and number of neurons that compose the spinal cord are related to body length, rather than to body mass or surface. Moreover, we show that although brain mass increases linearly with cord mass, the number of neurons in the brain increases with the number of neurons in the spinal cord raised to the power of 1.7. This faster addition of neurons to the brain than to the spinal cord is consistent with current views on how larger brains add complexity to the processing of environmental and somatic information.     

Updated neuronal scaling rules for the brains of Glires (rodents/lagomorphs)

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.     

Not all brains are made the same: new views on brain scaling in evolution

Evolution has generated mammalian brains that vary by a factor of over 100,000 in mass. Despite such tremendous diversity, brain scaling in mammalian evolution has tacitly been considered a homogeneous phenomenon in terms of numbers of neurons, neuronal density, and the ratio between glial and neuronal cells, with brains of different sizes viewed as similarly scaled-up or scaled-down versions of a shared basic plan. According to this traditional view, larger brains would have more neurons, smaller neuronal densities (and, hence, larger neurons), and larger glia/neuron ratios than smaller brains. Larger brains would also have a cerebellum that maintains its relative size constant and a cerebral cortex that becomes relatively larger to the point that brain evolution is often equated with cerebral cortical expansion. Here I review our recent data on the numbers of neuronal and nonneuronal cells that compose the brains of 28 mammalian species belonging to 3 large clades (Eulipotyphla, Glires, and Primata, plus the related Scandentia) and show that, contrary to the traditional notion of shared brain scaling, both the cerebral cortex and the cerebellum scale in size as clade-specific functions of their numbers of neurons. As a consequence, neuronal density and the glia/neuron ratio do not scale universally with structure mass and, most importantly, mammalian brains of a similar size can hold very different numbers of neurons. Remarkably, the increased relative size of the cerebral cortex in larger brains does not reflect an increased relative concentration of neurons in the structure. Instead, the cerebral cortex and cerebellum appear to gain neurons coordinately across mammalian species. Brain scaling in evolution, hence, should no longer be equated with an increasing dominance of the cerebral cortex but rather with the concerted addition of neurons to both the cerebral cortex and the cerebellum. Strikingly, all brains appear to gain nonneuronal cells in a similar fashion, with relatively constant nonneuronal cell densities. As a result, while brain size can no longer be considered a proxy for the number of brain neurons across mammalian brains in general, it is actually a very good proxy for the number of nonneuronal cells in the brain. Together, these data point to developmental mechanisms that underlie evolutionary changes in brain size in mammals: while the rules that determine how neurons are added to the brain during development have been largely free to vary in mammalian evolution across clades, the rules that determine how other cells are added in development have been mostly constrained and to this day remain largely similar both across brain structures and across mammalian groups.     

Primate prefrontal cortex evolution: human brains are the extreme of a lateralized ape trend

The prefrontal cortex is commonly associated with cognitive capacities related to human uniqueness: purposeful actions towards higher-level goals, complex social information processing, introspection, and language. Comparative investigations of the prefrontal cortex may thus shed more light on the neural underpinnings of what makes us human. Using histological data from 19 anthropoid primate species (6 apes including humans and 13 monkeys), we investigate cross-species relative size changes along the anterior (prefrontal) and posterior (motor) axes of the cytoarchitectonically defined frontal lobe in both hemispheres. Results reveal different scaling coefficients in the left versus right prefrontal hemisphere, suggest that the primary factor underlying the evolution of primate brain architecture is left hemispheric prefrontal hyperscaling, and indicate that humans are the extreme of a left prefrontal ape specialization in relative white to grey matter volume. These results demonstrate a neural adaptive shift distinguishing the ape from the monkey radiation possibly related to a cognitive grade shift between (great) apes and other primates.     

Distribution and cellular localization of adrenoleukodystrophy protein in human tissues: implications for X-linked adrenoleukodystrophy

Defects of adrenoleukodystrophy protein (ALDP) lead to X-linked adrenoleukodystrophy (X-ALD), a disorder mainly affecting the nervous system white matter and the adrenal cortex. In the present study, we examine the expression of ALDP in various human tissues and cell lines by multiple-tissue RNA expression array analysis, Western blot analysis, and immunohistochemistry. ALDP-encoding mRNA is most abundant in tissues with high energy requirements such as heart, muscle, liver, and the renal and endocrine systems. ALDP selectively occurs in specific cell types of brain (hypothalamus and basal nucleus of Meynert), kidney (distal tubules), skin (eccrine gland, hair follicles, and fibroblasts), colon (ganglion cells and epithelium), adrenal gland (zona reticularis and fasciculata), and testis (Sertoli and Leydig cells). In pituitary gland, ALDP is confined to adrenocorticotropin-producing cells and is significantly reduced in individuals receiving long term cortisol treatment. This might indicate a functional link between ALDP and proopiomelanocortin-derived peptide hormones.     

Functional tradeoffs in axonal scaling: implications for brain function

Like electrical wires, axons carry signals from place to place. However, unlike wires, because of the electrochemical mechanisms for generating and propagating action potentials, the performance of an axon is strongly linked to the costs of its construction and operation. As a consequence, the architecture of brain wiring is biophysically constrained to trade off speed and energetic efficiency against volume. Because the biophysics of axonal conduction is well studied, this tradeoff is amenable to quantitative analysis. In this framework, an examination of axon tract composition can yield insights into neural circuit function in regard to energetics, processing speed, spike timing precision, and average rates of neural activity.     

Ngfi-a immunoreactivity in the primate retina: implications for genetic regulation of plasticity

In rodents, enriched environments drive the expression of the immediate early gene NGFI-A, a regulator of the plasticity marker Synapsin I. Both proteins have been implicated as mediators of plasticity in the rat mammalian retina. In the present work immunocytochemistry directed against these proteins was used to explore their basal activity in the retina of a more visual species, the New World monkey Cebus apella. In contrast to rat, monkey retina displayed high basal expression of both NGFI-A and Synapsin I. The greatest number of NGFI-A -expressing cells was observed within the inner nuclear layer, although NGFI-A positive nuclei were also found in the ganglion cell layer. High levels of Synapsin I were found in the inner plexiform layer and outer plexiform layer. Our findings are consistent with the postulate that the retinas of highly visual animals may experience ongoing reorganization as part of normal visual processing, and that NGFI-A and Synapsin I may be well positioned to regulate some of these changes.     

A hypothesis on the primate neocortex evolution: column-multiplication hypothesis

A hypothesis is proposed, that the primate neocortex has evolved by the multiplication of cortical columns. As the column size is similar across primate species, it is considered that the columns have multiplied to expand the neocortex during primate evolution. This hypothesis would explain the expansion of neocortical sensory-motor-associational areas and multiple sensory and motor areas which had occurred during evolution. Further, the hypothesis predicts the existence of columns neutral for the fitness, genetic control upon the columns, and intraspecies variations of the columns.     

Bidding evidence for primate vocal learning and the cultural substrates for speech evolution

Speech evolution seems to defy scientific explanation. Progress on this front has been jammed in an entrenched orthodoxy about what great apes can and (mostly) cannot do vocally, an idea epitomized by the Kuypers/Jürgens hypothesis. Findings by great ape researchers paint, however, starkly different and more optimistic landscapes for speech evolution. Over twenty studies qualify as positive evidence for primate vocal (production) learning following accepted terminology. Additionally, the Kuypers/Jürgens hypothesis shows low etymological, empirical, and theoretical soundness. Great apes can produce novel voiced calls and voluntarily control their modification – observations supposedly impossible. Furthermore, no valid pretext justifies dismissing heuristically the production of new voiceless consonant-like calls by great apes. To underscore this point, new evidence is provided for a novel supra-genera voiceless call across all great ape species. Their vocal invention and vocal learning faculties are real and sufficiently potent to, at times, uphold vocal traditions. These data overpower conventional predicaments in speech evolution theory and will help to make new strides explaining why, among hominids, only humans developed speech.     

Neuron-astrocyte interactions: implications for cellular energetics and antioxidant levels

The interaction between astrocytes and neurons is examined from the standpoint of glutamate and glutathione (GSH) metabolism. These examples are outlined to provoke a reformulation of concepts of the inter-dependence between these 2 cell types, not only in terminating excitotoxicity, but also in assuring proper energetics and neuromodulation by astrocytic removal of glutamate via the astrocyte-specific glutamate transporters, GLT1 and GLAST. In addition, the role of astrocytes in the synthesis of neuronal GSH is detailed. The neuron-astrocyte interaction permits widely divergent aspects of brain energetics and modulation, and undoubtedly brain pathology where the functional unit is altered. Testing the developmental effects of compounds on this interaction is warranted and likely to establish the mechanisms by which it is compromised in a variety of disease states.     

Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer's disease

The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age.     

The primate amygdala and the neurobiology of social behavior: implications for understanding social anxiety.

The amygdala has long been implicated in the mediation of emotional and social behaviors. Because there are very few human subjects with selective bilateral damage of the amygdala, much of the evidence for these functional associations has come from studies employing animal subjects. Macaque monkeys live in complex, highly organized social groups that are characterized by stable and hierarchical relationships among individuals who engage in complex forms of social communication, such as facial expressions. Understanding the role of the amygdala in animals that display a level of social sophistication approaching that of humans will help in understanding the amygdala's role in human social behavior and in psychopathology such as social anxiety. Selective bilateral lesions of the amygdala in mature macaque monkeys result in a lack of fear responses to inanimate objects and a "socially uninhibited" pattern of behavior. These results imply that the amygdala functions as a protective "brake" on engagement of objects or organisms while an evaluation of potential threat is carried out. They also suggest that social anxiety may be a dysregulation or hyperactivity of the amygdala's evaluative process. Finally, recent data from developmental studies raise the possibility that, at least at some developmental stages, fear in social contexts may be subserved by different brain regions than fear of inanimate objects.     

Cytoarchitectonic heterogeneity of the primate neostriatum: Subdivision into island and matrix cellular compartments

The cytoarchitecture of the caudate nucleus was examined in Nisslstained sections from rhesus monkeys, in some of which the corticostriatal terminals had also been labeled by anterograde transport of tritiated amino acids injected into prefrontal cortex. The cytoarchitectonic analysis revealed the existence of two cellular compartments that could be distinguished on the basis of cell size, density, orientation, and tinctorial properties: (1) cell islands consisting of approximately 1,500 to 15,000 densely packed neurons that form aggregates of variable shapes and sizes embedded in (2) a matrix compartment of slightly larger and more loosely packed neurons that comprise the remaining and greater part of the caudate nucleus. In coronal sections, cellular islands appear mostly as round or elliptically shaped areas, 300–600 μm in diameter, but can assume more elongated and complex forms particularly in the sagittal and horizontal planes. They are encircled by fibers arranged in a thin, cell-sparse capsule that sets them apart from the matrix compartment. Analysis of cellular organization and corticostriatal connections in counterstained autoradiograms indicates that the prefrontal cortex projects only to the matrix zone and not to the territory occupied by island cells. Therefore, according to present observations the neostriatum in primates should be viewed as a cytoarchitectonically heterogeneous structure composed of at least two distinct cellular compartments with specific connectivity. These compartments may be related to the histochemical and functional diversity of the neostriatum.     

Multiple anatomical systems embedded within the primate medial temporal lobe: implications for hippocampal function

A review of medial temporal lobe connections reveals three distinct groupings of hippocampal efferents. These efferent systems and their putative memory functions are: (1) The 'extended-hippocampal system' for episodic memory, which involves the anterior thalamic nuclei, mammillary bodies and retrosplenial cortex, originates in the subicular cortices, and has a largely laminar organisation; (2) The 'rostral hippocampal system' for affective and social learning, which involves prefrontal cortex, amygdala and nucleus accumbens, has a columnar organisation, and originates from rostral CA1 and subiculum; (3) The 'reciprocal hippocampal-parahippocampal system' for sensory processing and integration, which originates from the length of CA1 and the subiculum, and is characterised by columnar, connections with reciprocal topographies. A fourth system, the 'parahippocampal-prefrontal system' that supports familiarity signalling and retrieval processing, has more widespread prefrontal connections than those of the hippocampus, along with different thalamic inputs. Despite many interactions between these four systems, they may retain different roles in memory which when combined explain the importance of the medial temporal lobe for the formation of declarative memories.     

Upregulation of the immediate early gene arc in the brains of rats exposed to environmental enrichment: implications for molecular plasticity.

Exposure to an enriched environment, a procedure that induces plasticity in the cerebral cortex, is associated with pronounced morphological changes, including higher density of dendritic spines, enlargement of synaptic boutons, and other putative correlates of altered neurotransmission. Recently, it has been demonstrated that animals reared in an enriched environment setting for 3 weeks have less neuronal damage as a result of seizures and have decreased rates of spontaneous apoptosis. Even though clear morphological modifications are observed in the cerebral cortex of animals exposed to heightened environmental complexity, the molecular mechanisms that underlie such modifications are yet to be described. In the present work, we investigated the expression of the immediate early gene arc in the cortex of animals exposed to an enriched environment. Animals were exposed daily, for 1 h, to an enriched environment, for a total period of 3 weeks. Brains were processed for in-situ hybridization against arc mRNA. We found a marked upregulation of arc mRNA in the cerebral cortex of animals exposed to the enriched environment, when compared to undisturbed controls, an effect that was most pronounced in cortical layers III and V. Animals in an additional control group that were handled for 5 min daily, displayed intermediate levels of arc mRNA. Furthermore, arc expression was upregulated in the CA1, CA2 and CA3 hippocampal subfields and in the striatum, but to a lesser extent in the dentate gyrus of animals exposed to an enriched environment, as compared to the two control groups. Our results support the association between the upregulation of the immediate early gene arc and plasticity-associated anatomical changes in the cerebral cortex of the adult mammal.     

Genomics and the human genome project: implications for psychiatry

In the past decade the Human Genome Project has made extraordinary strides in understanding of fundamental human genetics. The complete human genetic sequence has been determined, and the chromosomal location of almost all human genes identified. Presently, a large international consortium, the HapMap Project, is working to identify a large portion of genetic variation in different human populations and the structure and relationship of these variants to each other. The Human Genome Project has approached human genetics on a scale not previously seen in biology. This has been made possible by dramatic advances in high throughput technology and bio-informatics. Tools such as gene chips and micro-arrays have spawned an entirely new strategy to examine the function and expression of genes in a massively parallel fashion. Together these tools have dramatically advanced our knowledge about the human genome. They promise powerful new approaches to complex genetic traits such as psychiatric illness. The goals and progress of the Human Genome Project and the technology involved are reviewed. The implications of this science for psychiatric genetics are discussed.