Comparative Neuroanatomy Research Articles

Does a Vertebrate Morphotype of Pallial Subdivisions Really Exist?

Comparative neuroanatomists have long sought to determine which part of the pallium in nonmammals is homologous to the mammalian neocortex. A number of similar connectivity patterns across species have led to the idea that the basic organization of the vertebrate brain is relatively conserved; thus, efforts of the last decades have been focused on determining a vertebrate "morphotype" - a model comprising the characteristics believed to have been present in the last common ancestor of all vertebrates. The endeavor to determine the vertebrate morphotype has been riddled with controversies due to the extensive morphological diversity of the pallium among vertebrate taxa. Nonetheless, most proposed scenarios of pallial homology are variants of a common theme where the vertebrate pallium is subdivided into subdivisions homologous to the hippocampus, neocortex, piriform cortex, and amygdala, in a one-to-one manner. We review the rationales of major propositions of pallial homology and identify the source of the discrepancies behind different hypotheses. We consider that a source of discrepancies is the prevailing assumption that there is a single "morphotype of the pallial subdivisions" throughout vertebrates. Instead, pallial subdivisions present in different taxa probably evolved independently in each lineage. We encounter discrepancies when we search for a single morphotype of subdivisions across vertebrates. These discrepancies can be resolved by considering that several subdivisions within the pallium were established after the divergence of the different lineages. The differences of pallial organization are especially remarkable between actinopterygians (including teleost fishes) and other vertebrates. Thus, the prevailing notion of a simple one-to-one homology between the mammalian and teleost pallia needs to be reconsidered.

Volumetric study on sheep brain using stereology technique

AbstractThree‐dimensional morphometric data better show the structural and functional characteristics of the brain. The objective of this study was to estimate the volume of the cerebral structures of the sheep using design‐based stereology. The brains of five sheep were used, fixed in formalin 10% and embedded in agar 6%. An average of 10–12 slab was obtained from each brain. All slabs were stained using Mulligan's method and photographs were recorded. The volume of the brain and its structures were estimated using the Cavalieri's estimator and the point counting system. The total volume was 70604.8 ± 132.45 mm3. The volume fractions of the grey and white matters were calculated as 42.55 ± 0.21% and 24.23 ± 0.51% of the whole brain, respectively. The fractional volume of the caudate nucleus and claustrum were estimated at 2.39 ± 0.08% and at 1.008 ± 0.057% of total brain volume. The volumes of corpus callosum, internal capsule and external capsule were 1.24 ± 0.053%, 3.63 ± 0.22% and 0.698 ± 0.049% of total cerebral volume, respectively. These data could help improve the veterinary comparative neuroanatomy knowledge and development of experimental studies in the field.

An Approach to Evolutionary Sociology and its Implications for Theorizing on Socio-Cultural Evolution

A theoretical research program is outlined that seeks to use the Modern Synthesis in explaining human evolution, but also recognizes its limitations in explaining the evolution of socio-cultural systems. The universe, from a human perspective, is composed of physical, biological, and socio-cultural dimensions, each revealing unique properties and dynamics. In the case of the socio-cultural universe, modern evolutionary theory is relevant for some explanations, but not to the degree assumed by socio-biology, evolutionary psychology, and even co-evolutionary models. The program proposed is built around social network theory, cladistic analysis, and comparative neuro-anatomy, and outlines where biological analysis is appropriate and useful. An understanding of the biological basis of human behavior will allow sociologists to develop theoretical approaches to explaining the emergent properties of the socio-cultural universe. The strategy outlined will allow us to see what a mature evolutionary sociology can do: develop abstract theoretical laws about the dynamics of selection on socio-cultural formations in human societies.

Comparative MRI analysis of the forebrain of three sauropsida models

The study of the brain by magnetic resonance imaging (MRI) allows to obtain detailed anatomical images, useful to describe specific encephalic structures and to analyze possible variabilities. It is widely used in clinical practice and is becoming increasingly used in veterinary medicine, even in exotic animals; however, despite its potential, its use in comparative neuroanatomy studies is still incipient. It is a technology that in recent years has significantly improved anatomical resolution, together with the fact that it is non-invasive and allows for systematic comparative analysis. All this makes it particularly interesting and useful in evolutionary neuroscience studies, since it allows for the analysis and comparison of brains of rare or otherwise inaccessible species. In the present study, we have analyzed the prosencephalon of three representative sauropsid species, the turtle Trachemys scripta (order Testudine), the lizard Pogona vitticeps (order Squamata) and the snake Python regius (order Squamata) by MRI. In addition, we used MRI sections to analyze the total brain volume and ventricular system of these species, employing volumetric and chemometric analyses together. The raw MRI data of the sauropsida models analyzed in the present study are available for viewing and downloading and have allowed us to produce an atlas of the forebrain of each of the species analyzed, with the main brain regions. In addition, our volumetric data showed that the three groups presented clear differences in terms of total and ventricular brain volumes, particularly the turtles, which in all cases presented distinctive characteristics compared to the lizards and snakes.

Neuropil Variation in the Prefrontal, Motor, and Visual Cortex of Six Felids

Introduction: Felids have evolved a specialized suite of morphological adaptations for obligate carnivory. Although the musculoskeletal anatomy of the Felidae has been studied extensively, the comparative neuroanatomy of felids is relatively unexplored. Little is known about how variation in the cerebral anatomy of felids relates to species-specific differences in sociality, hunting strategy, or activity patterns. Methods: We quantitatively analyzed neuropil variation in the prefrontal, primary motor, and primary visual cortices of six species of Felidae (Panthera leo, Panthera uncia, Panthera tigris, Panthera leopardus, Acinonyx jubatus, Felis sylvestris domesticus) to investigate relationships with brain size, neuronal cell parameters, and select behavioral and ecological factors. Neuropil is the dense, intricate network of axons, dendrites, and synapses in the brain, playing a critical role in information processing and communication between neurons. Results: There were significant species and regional differences in neuropil proportions, with African lion, cheetah, and tiger having more neuropil in all three cortical regions in comparison to the other species. Based on regression analyses, we find that the increased neuropil fraction in the prefrontal cortex supports social and behavioral flexibility, while in the primary motor cortex, this facilitates the neural activity needed for hunting movements. Greater neuropil fraction in the primary visual cortex may contribute to visual requirements associated with diel activity patterns. Conclusion: These results provide a cross-species comparison of neuropil fraction variation in the Felidae, particularly the understudied Panthera, and provide evidence for convergence of the neuroanatomy of Panthera and cheetahs.

Comparative neuroanatomy of the central nervous system in web-building and cursorial hunting spiders.

Spiders (Araneae) include cursorial species that stalk their prey and more stationary species that use webs for prey capture. While many cursorial hunting spiders rely on visual cues, web-building spiders use vibratory cues (mechanosensation) for prey capture. We predicted that the differences in primary sensory input between the species are mirrored by differences in the morphology/architecture of the central nervous system (CNS). Here, we investigated the CNS anatomy of four spider species, two cursorial hunters Pardosa amentata (Lycosidae) and Marpissa muscosa (Salticidae), and two web-building hunters Argiope bruennichi (Araneidae) and Parasteatoda tepidariorum (Theridiidae). Their CNS was analyzed using Bodian silver impregnations, immunohistochemistry, and microCT analysis. We found that there are major differences between species in the secondary eye pathway of the brain that pertain to first-order, second-order, and higher order brain centers (mushroom bodies [MB]). While P. amentata and M. muscosa have prominent visual neuropils and MB, these are much reduced in the two web-building species. Argiope bruennichi lacks second-order visual neuropils but has specialized photoreceptors that project into two distinct visual neuropils, and P. tepidariorum lacks MB, suggesting that motion vision might be absent in this species. Interestingly, the differences in the ventral nerve cord are much less pronounced, but the web-building spiders have proportionally larger leg neuropils than the cursorial spiders. Our findings suggest that the importance of visual information is much reduced in web-building spiders, compared to cursorial spiders, while processing of mechanosensory information requires the same major circuits in both web-building and cursorial hunting spiders.

Comparative Neuroanatomy of Descending Neurons in Supraesophageal Ganglia of Cockroaches of the Family Blaberidae

Comparative Neuroanatomy of Descending Neurons in Supraesophageal Ganglia of Cockroaches of the Family Blaberidae

Comparative Neuroanatomy of Pediveliger Larvae of Various Bivalves from the Sea of Japan.

Here, we describe the nervous system structures from pediveligers of eight bivalve species (Callista brevisiphonata, Mactromeris polynyma, Crenomytilus grayanus, Kellia japonica, Mizuhopecten yessoensis, and Azumapecten farreri) with different modes of life in their adult stages, corresponding to the ecological niches that they occupy (burrowing, cemented, byssally attached, and mobile forms). We have identified neuromorphological features of the central and peripheral nervous systems in larval bivalves. We show that the unpaired sensory apical organ is still present in pediveligers along with the developing paired cerebral ganglia characteristic of an adult mollusk. Pediveligers have the pleural ganglia connected to the pedal ganglia via the pedal nerve cords and to the visceral ganglia via the lateral nerve cords. We have found a number of structures of the peripheral nervous system whose presence varies between pediveligers of different species. Mactromeris, Callista, and Pododesmus have 5-HT-immunopositive stomatogastric neurons, whereas the Yesso and Farrer's scallops have an FMRFamide-immunopositive enteric nervous system. The innervation of the anterior part of the velum is connected to a system of the apical organ and cerebral ganglia, and the innervation of the posterior part is connected to the visceral ganglia. Most differences in the structure of the peripheral elements of the nervous system are species-specific and weakly depend on the ecological niche that pediveligers occupy.

Introduction to Techniques Used to Study Mosquito Neuroanatomy and Neural Circuitry.

Mosquitoes transmit deadly pathogens from person to person as they obtain the blood meal that is essential for their life cycle. Female mosquitoes of many species are unable to reproduce without consuming protein that they obtain from blood. This developmental stage makes them highly efficient disease vectors of deadly pathogens. They can transmit pathogens between members of the same species and different species that can provide a route for evolving zoonotic viruses to jump from animals to humans. One possible way to develop novel strategies to combat pathogen transmission by mosquitoes is to study the sensory systems that drive mosquito reproductive behaviors, in particular the neural architecture and circuits of mosquito sensory afferent neurons, the central circuits that process sensory information, and the downstream circuits that drive reproductive behaviors. The study of mosquito neuroanatomy and circuitry also benefits basic neuroscience, allowing for comparative neuroanatomy in insect species, which has great value in the current model species-heavy landscape of neuroscience. Here, we introduce two important techniques that are used to study neuroanatomy and neural circuitry-namely, immunofluorescent labeling and neural tracing. We describe how to apply these approaches to study mosquito neuroanatomy and describe considerations for researchers using the techniques.

Systematic cortical thickness and curvature patterns in primates

Humans are known to have significant and consistent differences in thickness throughout the cortex, with thick outer gyral folds and thin inner sulcal folds. Our previous work has suggested a mechanical basis for this thickness pattern, with the forces generated during cortical folding leading to thick gyri and thin sulci, and shown that cortical thickness varies along a gyral–sulcal spectrum in humans. While other primate species are expected to exhibit similar patterns of cortical thickness, it is currently unknown how these patterns scale across different sizes, forms, and foldedness. Among primates, brains vary enormously from roughly the size of a grape to the size of a grapefruit, and from nearly smooth to dramatically folded; of these, human brains are the largest and most folded. These variations in size and form make comparative neuroanatomy a rich resource for investigating common trends that transcend differences between species. In this study, we examine 12 primate species in order to cover a wide range of sizes and forms, and investigate the scaling of their cortical thickness relative to the surface geometry. The 12 species were selected due to the public availability of either reconstructed surfaces and/or population templates. After obtaining or reconstructing 3D surfaces from publicly available neuroimaging data, we used our surface-based computational pipeline (https://github.com/mholla/curveball) to analyze patterns of cortical thickness and folding with respect to size (total surface area), geometry (i.e. curvature, shape, and sulcal depth), and foldedness (gyrification). In all 12 species, we found consistent cortical thickness variations along a gyral–sulcal spectrum, with convex shapes thicker than concave shapes and saddle shapes in between. Furthermore, we saw an increasing thickness difference between gyri and sulci as brain size increases. Our results suggest a systematic folding mechanism relating local cortical thickness to geometry. Finally, all of our reconstructed surfaces and morphometry data are available for future research in comparative neuroanatomy.

Mapping the branching pattern of the middle cerebral artery in the camel (Camelus dromedarius): a comprehensive anatomical analysis.

The complex branching structure of the middle cerebral artery serves as a crucial component in the blood supply to the cerebral cortex, playing a key role in sustaining brain function and overall neurological health in mammals. A thorough understanding of the branching structure of the middle cerebral artery is required for the advancement of veterinary medicine and neuroscience research. In this study, we provide the first comprehensive anatomical analysis of the branching structure of the middle cerebral artery (MCA) in the dromedary brain. To date, no study has examined the MCA branches in dromedaries. By examining 80 cerebral hemispheres from freshly slaughtered male dromedary camels aged 2-6 years, we aimed to explain the origin, course, and branching patterns of the MCA in the dromedary camel. Advanced casting techniques using colored latex, epoxy paint, and liquid plastic have been used to create precise renderings of the MCA structure. Our findings revealed that the MCA is the principal branch of the rostral cerebral artery and serves as the primary blood supply to the telencephalon in dromedaries. The main trunk of the MCA splits into several cortical branches, each supplying blood to a specific cerebral hemisphere. These branches comprise the rostral and caudal olfactory arteries; orbital artery; superior, middle, and inferior frontal arteries; rostral, middle, and caudal parietal arteries; and dorsal, middle, and ventral temporal arteries. This groundbreaking work considerably advances our understanding of the dromedary cerebrovascular system by providing insightful information on the anatomy and topography of the MCA. Our findings open new avenues for advancements in veterinary medicine and neuroscience research, with potential applications in the diagnosis and treatment of neurological disorders in dromedary camels. Furthermore, understanding the unique branching pattern of the MCA may have implications for comparative neuroanatomy and the evolution of cerebrovascular systems across species.

Evolution of cortical geometry and its link to function, behaviour and ecology

Studies in comparative neuroanatomy and of the fossil record demonstrate the influence of socio-ecological niches on the morphology of the cerebral cortex, but have led to oftentimes conflicting theories about its evolution. Here, we study the relationship between the shape of the cerebral cortex and the topography of its function. We establish a joint geometric representation of the cerebral cortices of ninety species of extant Euarchontoglires, including commonly used experimental model organisms. We show that variability in surface geometry relates to species’ ecology and behaviour, independent of overall brain size. Notably, ancestral shape reconstruction of the cortical surface and its change during evolution enables us to trace the evolutionary history of localised cortical expansions, modal segregation of brain function, and their association to behaviour and cognition. We find that individual cortical regions follow different sequences of area increase during evolutionary adaptations to dynamic socio-ecological niches. Anatomical correlates of this sequence of events are still observable in extant species, and relate to their current behaviour and ecology. We decompose the deep evolutionary history of the shape of the human cortical surface into spatially and temporally conscribed components with highly interpretable functional associations, highlighting the importance of considering the evolutionary history of cortical regions when studying their anatomy and function.

Endocast, brain, and bones: Correspondences and spatial relationships in squamates.

Vertebrate endocasts are widely used in the fields of paleoneurology and comparative neuroanatomy. The validity of endocranial studies is dependent upon the extent to which an endocast reflects brain morphology. Due to the variable neuroanatomical resolution of vertebrate endocasts, direct information about the brain morphology can be sometimes difficult to assess and needs to be investigated across lineages. Here, we employ X-ray computed tomography (CT), including diffusible iodine-based contrast-enhanced CT, to qualitatively compare brains and endocasts in different species of squamates. The relative position of the squamate brain within the skull, as well as the variability that may exist in such spatial relationships, was examined to help clarify the neurological regions evidence on their endocasts. Our results indicate that squamate endocasts provide variable representation of the brain, depending on species and neuroanatomical regions. The olfactory bulbs and peduncles, cerebral hemispheres, as well as the medulla oblongata represent the most easily discernable brain regions from squamate endocasts. In contrast, the position of the optic lobes, the ventral diencephalon and the pituitary may be difficult to determine depending on species. Finally, squamate endocasts provide very limited or no information about the cerebellum. The spatial relationships revealed here between the brain and the surrounding bones may help to identify each of the endocranial region. However, as one-to-one correspondences between a bone and a specific region appear limited, the exact delimitation of these regions may remain challenging according to species. This study provides a basis for further examination and interpretation of squamate endocast disparity.

Social complexity and brain evolution: insights from ant neuroarchitecture and genomics.

Brain evolution is hypothesized to be driven by requirements to adaptively respond to environmental cues and social signals. Diverse models describe how sociality may have influenced eusocial insect-brain evolution, but specific impacts of social organization and other selective forces on brain architecture have been difficult to distinguish. Here, we evaluate predictions derived from and/or inferences made by models of social organization concerning the effects of individual and collective behavior on brain size, structure, and function using results of neuroanatomical and genomic studies. In contrast to the predictions of some models, we find that worker brains in socially complex species have great behavioral and cognitive capacity. We also find that colony size, the evolution of worker physical castes, and task specialization affect brain size and mosaicism, supporting the idea that sensory, processingand motor requirements for behavioral performance select for adaptive allometries of functionally specialized brain centers. We review available transcriptomic and comparative genomic studies seeking to elucidate the molecular pathways functionally associated with social life and the genetic changes that occurred during the evolution of social complexity. We discuss ways forward, using comparative neuroanatomy, transcriptomics, and comparative genomics, to distinguish among multiple alternative explanations for the relationship between the evolution of neural systems and social complexity.

Comparative Neuroanatomy of the Mechanosensory Subgenual Organ Complex in the Peruvian Stick Insect, Oreophoetes peruana

The subgenual organ complex in the leg of Polyneoptera (Insecta) consists of several chordotonal organs specialized to detect mechanical stimuli from substrate vibrations and airborne sound. In stick insects (Phasmatodea), the subgenual organ complex contains the subgenual organ and the distal organ located distally to the subgenual organ. The subgenual organ is a highly sensitive detector for substrate vibrations. The distal organ has a characteristic linear organization of sensilla and likely also responds to substrate vibrations. Despite its unique combination of sensory organs, the neuroanatomy of the subgenual organ complex of stick insects has been investigated for only very few species so far. Phylogenomic analysis has established for Phasmatodea the early branching of the sister groups Oriophasmata, the Old World phasmids, and Occidophasmata, the New World phasmids. The species studied for the sensory neuroanatomy, including the Indian stick insect Carausius morosus, belong to the Old World stick insects. Here, the neuroanatomy of the subgenual organ complex is presented for a first species of the New World stick insects, the Peruvian stick insect Oreophoetes peruana. To document the sensory organs in the subgenual organ complex and their innervation pattern, and to compare these between females and males of this species and also to the Old World stick insects, axonal tracing is used. This study documents the same sensory organs for O. peruana, subgenual organ and distal organ, as in other stick insects. Between the sexes of this species, there are no notable differences in the neuroanatomy of their sensory organs. The innervation pattern of tibial nerve branches in O. peruana is identical to other stick insect species, although the innervation pattern of the subgenual organ by a single tibial nerve branch is simpler. The shared organization of the organs in the subgenual organ complex in both groups of Neophasmatodea (Old World and New World stick insects) indicates the sensory importance of the subgenual organ but also of the distal organ. Some variation exists in the innervation of the chordotonal organs in O. peruana though a common innervation pattern can be identified. The findings raise the question for the ancestral neuroanatomical organization and innervation in stick insects.

The Digital Brain Bank, an open access platform for post-mortem imaging datasets.

Post-mortem magnetic resonance imaging (MRI) provides the opportunity to acquire high-resolution datasets to investigate neuroanatomy and validate the origins of image contrast through microscopy comparisons. We introduce the Digital Brain Bank (open.win.ox.ac.uk/DigitalBrainBank), a data release platform providing open access to curated, multimodal post-mortem neuroimaging datasets. Datasets span three themes-Digital Neuroanatomist: datasets for detailed neuroanatomical investigations; Digital Brain Zoo: datasets for comparative neuroanatomy; and Digital Pathologist: datasets for neuropathology investigations. The first Digital Brain Bank data release includes 21 distinctive whole-brain diffusion MRI datasets for structural connectivity investigations, alongside microscopy and complementary MRI modalities. This includes one of the highest-resolution whole-brain human diffusion MRI datasets ever acquired, whole-brain diffusion MRI in fourteen nonhuman primate species, and one of the largest post-mortem whole-brain cohort imaging studies in neurodegeneration. The Digital Brain Bank is the culmination of our lab's investment into post-mortem MRI methodology and MRI-microscopy analysis techniques. This manuscript provides a detailed overview of our work with post-mortem imaging to date, including the development of diffusion MRI methods to image large post-mortem samples, including whole, human brains. Taken together, the Digital Brain Bank provides cross-scale, cross-species datasets facilitating the incorporation of post-mortem data into neuroimaging studies.

Alzheimer's Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model.

Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APP NL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APP NL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APP NL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APP NL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD

Refocusing neuroscience: moving away from mental categories and towards complex behaviours.

Mental terms—such as perception, cognition, action, emotion, as well as attention, memory, decision-making—are epistemically sterile. We support our thesis based on extensive comparative neuroanatomy knowledge of the organization of the vertebrate brain. Evolutionary pressures have moulded the central nervous system to promote survival. Careful characterization of the vertebrate brain shows that its architecture supports an enormous amount of communication and integration of signals, especially in birds and mammals. The general architecture supports a degree of ‘computational flexibility’ that enables animals to cope successfully with complex and ever-changing environments. Here, we suggest that the vertebrate neuroarchitecture does not respect the boundaries of standard mental terms, and propose that neuroscience should aim to unravel the dynamic coupling between large-scale brain circuits and complex, naturalistic behaviours.This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.

Elizabeth Crosby: Titan of Neuroanatomy and Friend of Neurosurgery.

Elizabeth Crosby (1888-1983) is a beloved and well-respected titan of neuroanatomy. Her contributions to our understanding of neuroanatomy are rooted in her seminal text, The Comparative Anatomy of the Nervous System of Vertebrates, Including Man, published in 1936, which is a masterful and comprehensive account of comparative neuroanatomy. Her later texts, Correlative Neurosurgery and Correlative Anatomy of the Nervous System, are standard reference texts to this day. Her mentorship of graduate students, close work with the University of Michigan neurosurgery department, and the quality of her research and scientific publications were recognized with many awards, culminating in the National Medal of Science presented by President Carter in 1980.

Using Tertiary Sulci to Map the "Cognitive Globe" of Prefrontal Cortex.

Stuss considered the human PFC as a "cognitive globe" [Stuss, D. T., & Benson, D. F. Neuropsychological studies of the frontal lobes. Psychological Bulletin, 95, 3-28, 1984] on which functions of the frontal lobe could be mapped. Here, we discuss classic and recent findings regarding the evolution, development, function, and cognitive role of shallow indentations or tertiary sulci in PFC, with the goal of using tertiary sulci to map the "cognitive globe" of PFC. First, we discuss lateral PFC (LPFC) tertiary sulci in classical anatomy and modern neuroimaging, as well as their development, with a focus on those within the middle frontal gyrus. Second, we discuss tertiary sulci in comparative neuroanatomy, focusing on primates. Third, we summarize recent findings showing the utility of tertiary sulci for understanding structural-functional relationships with functional network insights in ventromedial PFC and LPFC. Fourth, we revisit and update unresolved theoretical perspectives considered by C. Vogt and O. Vogt (Allgemeinere ergebnisse unserer hirnforschung. Journal für Psychologie und Neurologie, 25, 279-462, 1919) and F. Sanides (Structure and function of the human frontal lobe. Neuropsychologia, 2, 209-219, 1964) that tertiary sulci serve as landmarks for cortical gradients. Together, the consideration of these classic and recent findings indicate that tertiary sulci are situated in a unique position within the complexity of the "cognitive globe" of PFC: They are the smallest and shallowest of sulci in PFC, yet can offer insights that bridge spatial scales (microns to networks), modalities (functional connectivity to behavior), and species. As such, the map of tertiary sulci within each individual participant serves as a coordinate system specific to that individual on which functions may be further mapped. We conclude with new theoretical and methodological questions that, if answered in future research, will likely lead to mechanistic insight regarding the structure and function of human LPFC.