Tracing Modification to Cortical Circuits in Human and Nonhuman Primates from High-Resolution Tractography, Transcription, and Temporal Dimensions.

The neural circuits that support human cognition are a topic of enduring interest. Yet, there are limited tools available to map brain circuits in the human and nonhuman primate brain. We harnessed high-resolution diffusion MR tractography, anatomic, and transcriptomic data from individuals of either sex to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that frontal cortex circuitry development is extended in primates, and concomitant with an expansion in corticocortical pathways compared with mice in adulthood. Importantly, we found that these parameters varied relatively little across humans and studied primates. These data identify a surprising collection of conserved features in frontal cortex circuits across humans and Old World monkeys. Our work demonstrates that integrating transcriptional and structural data across temporal dimensions is a robust approach to trace the evolution of brain pathways in primates.SIGNIFICANCE STATEMENT Diffusion MR tractography is an exciting method to explore pathways, but there are uncertainties in the accuracy of reconstructed tracts. We broaden the repertoire of toolkits to enhance our ability to trace human brain pathways from diffusion MR tractography. Our integrative approach finds corresponding ages across species and transcriptionally defines neural circuits. We used this information to test for variation in circuit maturation across species and found a surprising constellation of similar features in frontal cortex neural circuits across humans and primates. Integrating across scales of biological organization expands the repertoire of tools available to study pathways in primates, which opens new avenues to study pathways in health and diseases of the human brain.

Mapping Human Brain Pathways: Challenges and Opportunities in the Integration of Scales.

The human brain is composed of a complex web of pathways. Diffusion magnetic resonance (MR) tractography is a neuroimaging technique that relies on the principle of diffusion to reconstruct brain pathways. Its tractography is broadly applicable to a range of problems as it is amenable for study in individuals of any age and from any species. However, it is well known that this technique can generate biologically implausible pathways, especially in regions of the brain where multiple fibers cross. This review highlights potential misconnections in two cortico-cortical association pathways with a focus on the aslant tract and inferior frontal occipital fasciculus. The lack of alternative methods to validate observations from diffusion MR tractography means there is a need to develop new integrative approaches to trace human brain pathways. This review discusses integrative approaches in neuroimaging, anatomical, and transcriptional variation as having much potential to trace the evolution of human brain pathways.

Cutting across structural and transcriptomic scales translates time across the lifespan in humans and chimpanzees.

How the unique capacities of human cognition arose in evolution is a question of enduring interest. It is still unclear which developmental programmes are responsible for the emergence of the human brain. The inability to determine corresponding ages between humans and apes has hampered progress in detecting developmental programmes leading to the emergence of the human brain. I harness temporal variation in anatomical, behavioural and transcriptional variation to determine corresponding ages from fetal to postnatal development and ageing, between humans and chimpanzees. This multi-dimensional approach results in 137 corresponding time points across the lifespan, from embryonic day 44 to approximately 55 years of age, in humans and their equivalent ages in chimpanzees. I used these data to test whether developmental programmes, such as the timeline of prefrontal cortex (PFC) maturation, previously claimed to differ between humans and chimpanzees, do so once variation in developmental schedules is controlled for. I compared the maturation of frontal cortex projections from structural magnetic resonance (MR) scans and from temporal variation in the expression of genes used to track long-range projecting neurons (i.e. supragranular-enriched genes) in chimpanzees and humans. Contrary to what has been suggested, the timetable of PFC maturation is not unusually extended in humans. This dataset, which is the largest with which to determine corresponding ages across humans and chimpanzees, provides a rigorous approach to control for variation in developmental schedules and to identify developmental programmes responsible for unique features of the human brain.

Brain Wiring and Supragranular-Enriched Genes Linked to Protracted Human Frontal Cortex Development.

The human frontal cortex is unusually large compared with many other species. The expansion of the human frontal cortex is accompanied by both connectivity and transcriptional changes. Yet, the developmental origins generating variation in frontal cortex circuitry across species remain unresolved. Nineteen genes that encode filaments, synapse, and voltage-gated channels are especially enriched in the supragranular layers of the human cerebral cortex, which suggests enhanced corticocortical projections emerging from layer III. We identify species differences in connections with the use of diffusion MR tractography as well as gene expression in adulthood and in development to identify developmental mechanisms generating variation in frontal cortical circuitry. We demonstrate that increased expression of supragranular-enriched genes in frontal cortex layer III is concomitant with an expansion in corticocortical pathways projecting within the frontal cortex in humans relative to mice. We also demonstrate that the growth of the frontal cortex white matter and transcriptional profiles of supragranular-enriched genes are protracted in humans relative to mice. The expansion of projections emerging from the human frontal cortex arises by extending frontal cortical circuitry development. Integrating gene expression with neuroimaging level phenotypes is an effective strategy to assess deviations in developmental programs leading to species differences in connections.

High Angular Resolution Diffusion MRI Reveals Conserved and Deviant Programs in the Paths that Guide Human Cortical Circuitry.

Diffusion magnetic resonance (MR) tractography represents a novel opportunity to investigate conserved and deviant developmental programs between humans and other species such as mice. To that end, we acquired high angular resolution diffusion MR scans of mice [embryonic day (E) 10.5 to postnatal week 4] and human brains [gestational week (GW) 17-30] at successive stages of fetal development to investigate potential evolutionary changes in radial organization and emerging pathways between humans and mice. We compare radial glial development as well as commissural development (e.g., corpus callosum), primarily because our findings can be integrated with previous work. We also compare corpus callosal growth trajectories across primates (i.e., humans and rhesus macaques) and rodents (i.e., mice). One major finding is that the developing cortex of humans is predominated by pathways likely associated with a radial glial organization at GW 17-20, which is not as evident in age-matched mice (E 16.5, 17.5). Another finding is that, early in development, the corpus callosum follows a similar developmental timetable in primates (i.e., macaques and humans) as in mice. However, the corpus callosum grows for an extended period of time in primates compared with rodents. Taken together, these findings highlight deviant developmental programs underlying the emergence of cortical pathways in the human brain.

Brain Plasticity in Humans and Model Systems: Advances, Challenges, and Future Directions.

Plasticity, and in particular, neurogenesis, is a promising target to treat and prevent a wide variety of diseases (e.g., epilepsy, stroke, dementia). There are different types of plasticity, which vary with age, brain region, and species. These observations stress the importance of defining plasticity along temporal and spatial dimensions. We review recent studies focused on brain plasticity across the lifespan and in different species. One main theme to emerge from this work is that plasticity declines with age but that we have yet to map these different forms of plasticity across species. As part of this effort, we discuss our recent progress aimed to identify corresponding ages across species, and how this information can be used to map temporal variation in plasticity from model systems to humans.

Closing the gap from transcription to the structural connectome enhances the study of connections in the human brain.

The brain is composed of a complex web of networks but we have yet to map the structural connections of the human brain in detail. Diffusion MR imaging is a high-throughput method that relies on the principle of diffusion to reconstruct tracts (ie, pathways) across the brain. Although diffusion MR tractography is an exciting method to explore the structural connectivity of the brain in development and across species, the tractography has at times led to questionable interpretations. There are at present few if any alternative methods to trace structural pathways in the human brain. Given these limitations and the potential of diffusion MR imaging to map the human connectome, it is imperative that we develop new approaches to validate neuroimaging techniques. I discuss our recent studies integrating neuroimaging with transcriptional and anatomical variation across humans and other species over the course of development and in adulthood. Developing a novel framework to harness the potential of diffusion MR tractography provides new and exciting opportunities to study the evolution of developmental mechanisms generating variation in connections and bridge the gap between model systems to humans.

Evolution of Brain Connections: Integrating Diffusion MR Tractography With Gene Expression Highlights Increased Corticocortical Projections in Primates.

Diffusion MR tractography permits investigating the 3D structure of cortical pathways as interwoven paths across the entire brain. We use high-resolution scans from diffusion spectrum imaging and high angular resolution diffusion imaging to investigate the evolution of cortical pathways within the euarchontoglire (i.e., primates, rodents) lineage. More specifically, we compare cortical fiber pathways between macaques (Macaca mulatta), marmosets (Callithrix jachus), and rodents (mice, Mus musculus). We integrate these observations with comparative analyses of Neurofilament heavy polypeptide (NEFH) expression across the cortex of mice and primates. We chose these species because their phylogenetic position serves to trace the early evolutionary history of the human brain. Our comparative analysis from diffusion MR tractography, cortical white matter scaling, and NEFH expression demonstrates that the examined primates deviate from mice in possessing increased long-range cross-cortical projections, many of which course across the anterior to posterior axis of the cortex. Our study shows that integrating gene expression data with diffusion MR data is an effective approach in identifying variation in connectivity patterns between species. The expansion of corticocortical pathways and increased anterior to posterior cortical integration can be traced back to an extension of neurogenetic schedules during development in primates.

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.

Expansion, folding, and abnormal lamination of the chick optic tectum after intraventricular injections of FGF2.

Comparative research has shown that evolutionary increases in brain region volumes often involve delays in neurogenesis. However, little is known about the influence of such changes on subsequent development. To get at this question, we injected FGF2--which delays cell cycle exit in mammalian neocortex--into the cerebral ventricles of chicks at embryonic day (ED) 4. This manipulation alters the development of the optic tectum dramatically. By ED7, the tectum of FGF2-treated birds is abnormally thin and has a reduced postmitotic layer, consistent with a delay in neurogenesis. FGF2 treatment also increases tectal volume and ventricular surface area, disturbs tectal lamination, and creates small discontinuities in the pia mater overlying the tectum. On ED12, the tectum is still larger in FGF2-treated embryos than in controls. However, lateral portions of the FGF2-treated tectum now exhibit volcano-like laminar disturbances that coincide with holes in the pia, and the caudomedial tectum exhibits prominent folds. To explain these observations, we propose that the tangential expansion of the ventricular surface in FGF2-treated tecta outpaces the expansion of the pial surface, creating abnormal mechanical stresses. Two alternative means of alleviating these stresses are tectal foliation and the formation of pial holes. The latter probably alter signaling gradients required for normal cell migration and may generate abnormal patterns of cerebrospinal fluid flow; both abnormalities would generate disturbances in tectal lamination. Overall, our findings suggest that evolutionary expansion of sheet-like, laminated brain regions requires a concomitant expansion of the pia mater.

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.

Helpless infants are learning a foundation model.

Humans have a protracted postnatal helplessness period, typically attributed to human-specific maternal constraints causing an early birth when the brain is highly immature. By aligning neurodevelopmental events across species, however, it has been found that humans are not born with especially immature brains compared with animal species with a shorter helpless period. Consistent with this, the rapidly growing field of infant neuroimaging has found that brain connectivity and functional activation at birth share many similarities with the mature brain. Inspired by machine learning, where deep neural networks also benefit from a 'helpless period' of pre-training, we propose that human infants are learning a foundation model: a set of fundamental representations that underpin later cognition with high performance and rapid generalisation.

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.

Transcription, structure, and organoids translate time across the lifespan of humans and great apes.

How the neural structures supporting human cognition developed and arose in evolution is an enduring question of interest. Yet, we still lack appropriate procedures to align ages across primates, and this lacuna has hindered progress in understanding the evolution of biological programs. We generated a dataset of unprecedented size consisting of 573 time points from abrupt and gradual changes in behavior, anatomy, and transcription across human and 8 nonhuman primate species. We included time points from diverse human populations to capture within-species variation in the generation of cross-species age alignments. We also extracted corresponding ages from organoids. The identification of corresponding ages across the lifespan of 8 primate species, including apes (e.g., orangutans, gorillas) and monkeys (i.e., marmosets, macaques), reveals that some biological pathways are extended in humans compared with some nonhuman primates. Notably, the human lifespan is unusually extended relative to studied nonhuman primates demonstrating that very old age is a phase of life in humans that does not map to other studied primate species. More generally, our work prompts a reevaluation in the choice of a model system to understand aging given very old age in humans is a period of life without a clear counterpart in great apes.

Evolutionary and genomic perspectives of brain aging and neurodegenerative diseases.

This chapter utilizes genomic concepts and evolutionary perspectives to further understand the possible links between typical brain aging and neurodegenerative diseases, focusing on the two most prevalent of these: Alzheimer's disease and Parkinson's disease. Aging is the major risk factor for these neurodegenerative diseases. Researching the evolutionary and molecular underpinnings of aging helps to reveal elements of the typical aging process that leave individuals more vulnerable to neurodegenerative pathologies. Very little is known about the prevalence and susceptibility of neurodegenerative diseases in nonhuman species, as only a few individuals have been observed with these neuropathologies. However, several studies have investigated the evolution of lifespan, which is closely connected with brain size in mammals, and insights can be drawn from these to enrich our understanding of neurodegeneration. This chapter explores the relationship between the typical aging process and the events in neurodegeneration. First, we examined how age-related processes can increase susceptibility to neurodegenerative diseases. Second, we assessed to what extent neurodegeneration is an accelerated form of aging. We found that while at the phenotypic level both neurodegenerative diseases and the typical aging process share some characteristics, at the molecular level they show some distinctions in their profiles, such as variation in genes and gene expression. Furthermore, neurodegeneration of the brain is associated with an earlier onset of cellular, molecular, and structural age-related changes. In conclusion, a more integrative view of the aging process, both from a molecular and an evolutionary perspective, may increase our understanding of neurodegenerative diseases.

Going beyond established model systems of Alzheimer's disease: companion animals provide novel insights into the neurobiology of aging.

Alzheimer's disease (AD) is characterized by brain plaques, tangles, and cognitive impairment. AD is one of the most common age-related dementias in humans. Progress in characterizing AD and other age-related disorders is hindered by a perceived dearth of animal models that naturally reproduce diseases observed in humans. Mice and nonhuman primates are model systems used to understand human diseases. Still, these model systems lack many of the biological characteristics of Alzheimer-like diseases (e.g., plaques, tangles) as they grow older. In contrast, companion animal models (cats and dogs) age in ways that resemble humans. Both companion animal models and humans show evidence of brain atrophy, plaques, and tangles, as well as cognitive decline with age. We embrace a One Health perspective, which recognizes that the health of humans is connected to those of animals, and we illustrate how such a perspective can work synergistically to enhance human and animal health. A comparative biology perspective is ideally suited to integrate insights across veterinary and human medical disciplines and solve long-standing problems in aging.