Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain.

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [11 C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [11 C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [11 C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [11 C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [11 C]UCB-J in PET studies. In addition, observation of low binding for [11 C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [11 C]UCB-J PET data.

Secondary somatosensory cortex of primates: beyond body maps, toward conscious self-in-the-world maps.

Recent human imaging studies have revealed the involvement of the secondary somatosensory cortex (SII) in processes that require high-level information integration, such as self-consciousness, social relations, whole body representation, and metaphorical extrapolations. These functions are far beyond its known role in the formation of body maps (even in their most complex forms), requiring the integration of different information modalities in addition to somatosensory information. However, no evidence of such complex processing seems to have been detected at the neuronal level in animal experiments, which would constitute a major discrepancy between human and non-human animals. This article scrutinizes this gap, introducing experimental evidence of human and non-human primates' SII functions set in context with their evolutionary significance and mechanisms, functionally situating the human SII as a primate brain. Based on the presented data, a new concept of a somatocentric holistic self is proposed, represented as a more comprehensive body-in-the-world map in the primate SII, taking into account evolutionary aspects that characterize the human SII and its implication in the emergence of self-consciousness. Finally, the idea of projection is introduced from the viewpoint of cognitive science, providing a logical explanation to bridge this gap between observed behavior and neurophysiological data.

Anterior Cingulate Pathways May Affect Emotions Through Orbitofrontal Cortex.

The anterior cingulate cortex (ACC) and posterior orbitofrontal cortex (pOFC) are associated with emotional regulation. These regions are old in phylogeny and have widespread connections with eulaminate neocortices, intricately linking areas associated with emotion and cognition. The ACC and pOFC have distinct cortical and subcortical connections and are also interlinked, but the pattern of their connections-which may be used to infer the flow of information between them-is not well understood. Here we found that pathways from ACC area 32 innervated all pOFC areas with a significant proportion of large and efficient terminals, seen at the level of the system and the synapse. The pathway from area 32 targeted overwhelmingly elements of excitatory neurons in pOFC, with few postsynaptic sites found on presumed inhibitory neurons. Moreover, pathways from area 32 originated mostly in the upper layers and innervated preferentially the middle-deep layers of the least differentiated pOFC areas, in a pattern reminiscent of feedforward communication. Pathway terminations from area 32 overlapped in the deep layers of pOFC with output pathways that project to the thalamus and the amygdala, and may have cascading downstream effects on emotional and cognitive processes and their disruption in psychiatric disorders.

Mapping complementary features of cross-species structural connectivity to construct realistic "Virtual Brains".

Modern systems neuroscience increasingly leans on large-scale multi-lab neuroinformatics initiatives to provide necessary capacity for biologically realistic modeling of primate whole-brain activity. Here, we present a framework to assemble primate brain's biologically plausible anatomical backbone for such modeling initiatives. In this framework, structural connectivity is determined by adding complementary information from invasive macaque axonal tract tracing and non-invasive human diffusion tensor imaging. Both modalities are combined by means of available interspecies registration tools and a newly developed Bayesian probabilistic modeling approach to extract common connectivity evidence. We demonstrate how this novel framework is embedded in the whole-brain simulation platform called The Virtual Brain (TVB). Hum Brain Mapp 38:2080-2093, 2017. © 2017 Wiley Periodicals, Inc.

Brain organization of gorillas reflects species differences in ecology.

Gorillas include separate eastern (Gorilla beringei) and western (Gorilla gorilla) African species that diverged from each other approximately 2 million years ago. Although anatomical, genetic, behavioral, and socioecological differences have been noted among gorilla populations, little is known about variation in their brain structure. This study examines neuroanatomical variation between gorilla species using structural neuroimaging. Postmortem magnetic resonance images were obtained of brains from 18 captive western lowland gorillas (Gorilla gorilla gorilla), 15 wild mountain gorillas (Gorilla beringei beringei), and 3 Grauer's gorillas (Gorilla beringei graueri) (both wild and captive). Stereologic methods were used to measure volumes of brain structures, including left and right frontal lobe gray and white matter, temporal lobe gray and white matter, parietal and occipital lobes gray and white matter, insular gray matter, hippocampus, striatum, thalamus, each hemisphere and the vermis of the cerebellum, and the external and extreme capsules together with the claustrum. Among the species differences, the volumes of the hippocampus and cerebellum were significantly larger in G. gorilla than G. beringei. These anatomical differences may relate to divergent ecological adaptations of the two species. Specifically, G. gorilla engages in more arboreal locomotion and thus may rely more on cerebellar circuits. In addition, they tend to eat more fruit and have larger home ranges and consequently might depend more on spatial mapping functions of the hippocampus.

Dynamic hyperpolarized carbon-13 MR metabolic imaging of nonhuman primate brain.

PURPOSE: To investigate hyperpolarized (13) C metabolic imaging methods in the primate brain that can be translated into future clinical trials for patients with brain cancer. METHODS: (13) C coils and pulse sequences designed for use in humans were tested in phantoms. Dynamic (13) C data were obtained from a healthy cynomolgus monkey brain using the optimized (13) C coils and pulse sequences. The metabolite kinetics were estimated from two-dimensional localized (13) C dynamic imaging data from the nonhuman primate brain. RESULTS: Pyruvate and lactate signal were observed in both the brain and the surrounding tissues with the maximum signal-to-noise ratio of 218 and 29 for pyruvate and lactate, respectively. Apparent rate constants for the conversion of pyruvate to lactate and the ratio of lactate to pyruvate showed a difference between brain and surrounding tissues. CONCLUSION: The feasibility of using hyperpolarized [1-(13) C]-pyruvate for assessing in vivo metabolism in a healthy nonhuman primate brain was demonstrated using a hyperpolarized (13) C imaging experimental setup designed for studying patients with brain tumors. The kinetics of the metabolite conversion suggests that this approach may be useful in future studies of human neuropathology.

Lineage-specific splicing regulation of MAPT gene in the primate brain.

Divergence of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is widespread in mammals, including primates, but the underlying mechanisms and functional impact are poorly understood. Here, we modeled cassette exon inclusion in primate brains as a quantitative trait and identified 1,170 (∼3%) exons with lineage-specific splicing shifts under stabilizing selection. Among them, microtubule-associated protein tau (MAPT) exons 2 and 10 underwent anticorrelated, two-step evolutionary shifts in the catarrhine and hominoid lineages, leading to their present inclusion levels in humans. The developmental-stage-specific divergence of exon 10 splicing, whose dysregulation can cause frontotemporal lobar degeneration (FTLD), is mediated by divergent distal intronic MBNL-binding sites. Competitive binding of these sites by CRISPR-dCas13d/gRNAs effectively reduces exon 10 inclusion, potentially providing a therapeutically compatible approach to modulate tau isoform expression. Our data suggest adaptation of MAPT function and, more generally, a role for AS in the evolutionary expansion of the primate brain.

Structural MRI analysis of age-related changes and sex differences in marmoset brain volume.

The field of aging biology, which aims to extend healthy lifespans and prevent age-related diseases, has turned its focus to the Callithrix jacchus (common marmoset) to understand the aging process better. This study utilized magnetic resonance imaging (MRI) to non-invasively analyze the brains of 216 marmosets, investigating age-related changes in brain structure; the relationship between body weight and brain volume; and potential differences between males and females. The key findings revealed that, similar to humans, Callithrix jacchus experiences a reduction in total intracranial volume, cortex, subcortex, thalamus, and cingulate volumes as they age, highlighting site-dependent changes in brain tissue. Notably, the study also uncovered sex differences in cerebellar volume. These insights into the structural connectivity and volumetric changes in the marmoset brain throughout aging contribute to accumulating valuable knowledge in the field, promising to inform future aging research and interventions for enhancing healthspan.

Continuous immunosuppression is required for suppressing immune responses to xenografts in non-human primate brains.

Continuous immunosuppression has been widely used in xenografts into non-human primate brains. However, how immune responses change after transplantation in host brains under continuous immunosuppressive administration and whether immunosuppression can be withdrawn to mitigate side effects remain unclear. Human induced neural stem/progenitor cells (iNPCs) have shown long-term survival and efficient neuronal differentiation in primate brains. Here, we evaluate the immune responses in primate brains triggered by human grafts. The results show that the immune responses, including the evident activation of microglia and the strong infiltration of lymphocytes (both T- and B-cells), are caused by xenografts at 4 months post transplantation (p.t.), but significantly reduced at 8 months p.t. under continuous administration of immunosuppressant Cyclosporin A. However, early immunosuppressant withdrawal at 5 months p.t. results in severe immune responses at 10 months p.t. These results suggest that continuous long-term immunosuppression is required for suppressing immune responses to xenografts in primate brains.

Phylogenetic reduction of the magnocellular red nucleus in primates and inter-subject variability in humans.

Introduction: The red nucleus is part of the motor system controlling limb movements. While this seems to be a function common in many vertebrates, its organization and circuitry have undergone massive changes during evolution. In primates, it is sub-divided into the magnocellular and parvocellular parts that give rise to rubrospinal and rubro-olivary connection, respectively. These two subdivisions are subject to striking variation within the primates and the size of the magnocellular part is markedly reduced in bipedal primates including humans. The parvocellular part is part of the olivo-cerebellar circuitry that is prominent in humans. Despite the well-described differences between species in the literature, systematic comparative studies of the red nucleus remain rare. Methods: We therefore mapped the red nucleus in cytoarchitectonic sections of 20 primate species belonging to 5 primate groups including prosimians, new world monkeys, old world monkeys, non-human apes and humans. We used Ornstein-Uhlenbeck modelling, ancestral state estimation and phylogenetic analysis of covariance to scrutinize the phylogenetic relations of the red nucleus volume. Results: We created openly available high-resolution cytoarchitectonic delineations of the human red nucleus in the microscopic BigBrain model and human probabilistic maps that capture inter-subject variations in quantitative terms. Further, we compared the volume of the nucleus across primates and showed that the parvocellular subdivision scaled proportionally to the brain volume across the groups while the magnocellular part deviated significantly from the scaling in humans and non-human apes. These two groups showed the lowest size of the magnocellular red nucleus relative to the whole brain volume and the largest relative difference between the parvocellular and magnocellular subdivision. Discussion: That is, the red nucleus has transformed from a magnocellular-dominated to a parvocellular-dominated station. It is reasonable to assume that these changes are intertwined with evolutionary developments in other brain regions, in particular the motor system. We speculate that the interspecies variations might partly reflect the differences in hand dexterity but also the tentative involvement of the red nucleus in sensory and cognitive functions.

Primate brain pattern-based automated Alzheimer's disease detection model using EEG signals.

Electroencephalography (EEG) may detect early changes in Alzheimer's disease (AD), a debilitating progressive neurodegenerative disease. We have developed an automated AD detection model using a novel directed graph for local texture feature extraction with EEG signals. The proposed graph was created from a topological map of the macroscopic connectome, i.e., neuronal pathways linking anatomo-functional brain segments involved in visual object recognition and motor response in the primate brain. This primate brain pattern (PBP)-based model was tested on a public AD EEG signal dataset. The dataset comprised 16-channel EEG signal recordings of 12 AD patients and 11 healthy controls. While PBP could generate 448 low-level features per one-dimensional EEG signal, combining it with tunable q-factor wavelet transform created a multilevel feature extractor (which mimicked deep models) to generate 8,512 (= 448 × 19) features per signal input. Iterative neighborhood component analysis was used to choose the most discriminative features (the number of optimal features varied among the individual EEG channels) to feed to a weighted k-nearest neighbor (KNN) classifier for binary classification into AD vs. healthy using both leave-one subject-out (LOSO) and tenfold cross-validations. Iterative majority voting was used to compute subject-level general performance results from the individual channel classification outputs. Channel-wise, as well as subject-level general results demonstrated exemplary performance. In addition, the model attained 100% and 92.01% accuracy for AD vs. healthy classification using the KNN classifier with tenfold and LOSO cross-validations, respectively. Our developed multilevel PBP-based model extracted discriminative features from EEG signals and paved the way for further development of models inspired by the brain connectome.

Human Brain Project Partnering Projects Meeting: Status Quo and Outlook.

As the European Flagship Human Brain Project (HBP) ends in September 2023, a meeting dedicated to the Partnering Projects (PPs), a collective of independent research groups that partnered with the HBP, was held on September 4-7, 2022. The purpose of this meeting was to allow these groups to present their results, reflect on their collaboration with the HBP and discuss future interactions with the European Research Infrastructure (RI) EBRAINS that has emerged from the HBP. In this report, we share the tour-de-force that the Partnering Projects that were present in the meeting have made in furthering knowledge concerning various aspects of Brain Research with the HBP. We describe briefly major achievements of the HBP Partnering Projects in terms of a systems-level understanding of the functional architecture of the brain and its possible emulation in artificial systems. We then recapitulate open discussions with EBRAINS representatives about the evolution of EBRAINS as a sustainable Research Infrastructure for the Partnering Projects after the HBP, and also for the wider scientific community.

Von Economo Neurons - Primate-Specific or Commonplace in the Mammalian Brain?

The pioneering work by von Economo in 1925 on the cytoarchitectonics of the cerebral cortex revealed a specialized and unique cell type in the adult human fronto-insular (FI) and anterior cingulate cortex (ACC). In modern studies, these neurons are termed von Economo neurons (VENs). In his work, von Economo described them as stick, rod or corkscrew cells because of their extremely elongated and relatively thin cell body clearly distinguishable from common oval or spindle-shaped infragranular principal neurons. Before von Economo, in 1899 Cajal depicted the unique somato-dendritic morphology of such cells with extremely elongated soma in the FI. However, although VENs are increasingly investigated, Cajal's observation is still mainly being neglected. On Golgi staining in humans, VENs have a thick and long basal trunk with horizontally oriented terminal branching (basilar skirt) from where the axon arises. They are clearly distinguishable from a spectrum of modified pyramidal neurons found in infragranular layers, including oval or spindle-shaped principal neurons. Spindle-shaped cells with highly elongated cell body were also observed in the ACC of great apes, but despite similarities in soma shape, their dendritic and axonal morphology has still not been described in sufficient detail. Studies identifying VENs in non-human species are predominantly done on Nissl or anti-NeuN staining. In most of these studies, the dendritic and axonal morphology of the analyzed cells was not demonstrated and many of the cells found on Nissl or anti-NeuN staining had a cell body shape characteristic for common oval or spindle-shaped cells. Here we present an extensive literature overview on VENs, which demonstrates that human VENs are specialized elongated principal cells with unique somato-dendritic morphology found abundantly in the FI and ACC of the human brain. More research is needed to properly evaluate the presence of such specialized cells in other primates and non-primate species.

Five Breakthroughs: A First Approximation of Brain Evolution From Early Bilaterians to Humans.

Retracing the evolutionary steps by which human brains evolved can offer insights into the underlying mechanisms of human brain function as well as the phylogenetic origin of various features of human behavior. To this end, this article presents a model for interpreting the physical and behavioral modifications throughout major milestones in human brain evolution. This model introduces the concept of a "breakthrough" as a useful tool for interpreting suites of brain modifications and the various adaptive behaviors these modifications enabled. This offers a unique view into the ordered steps by which human brains evolved and suggests several unique hypotheses on the mechanisms of human brain function.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in a chimpanzee (Pan troglodytes) brain.

We examined the number, distribution, and immunoreactivity of the infracortical white matter neuronal population, also termed white matter interstitial cells (WMICs), throughout the telencephalic white matter of an adult female chimpanzee. Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most numerous and dense close to the inner border of cortical layer VI, decreasing significantly in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed an estimate of approximately 137.2 million WMICs within the infracortical white matter of the chimpanzee brain studied. Immunostaining revealed subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS, approximately 14.4 million in number), calretinin (CR, approximately 16.7 million), very few WMICs containing parvalbumin (PV), and no calbindin-immunopositive neurons. The nNOS, CR, and PV immunopositive WMICs, possibly all inhibitory neurons, represent approximately 22.6% of the total WMIC population. As the white matter is affected in many cognitive conditions, such as schizophrenia, autism, epilepsy, and also in neurodegenerative diseases, understanding these neurons across species is important for the translation of findings of neural dysfunction in animal models to humans. Furthermore, studies of WMICs in species such as apes provide a crucial phylogenetic context for understanding the evolution of these cell types in the human brain.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in the brains of a southern lesser galago, a black-capped squirrel monkey, and a crested macaque.

In the current study, we examined the number, distribution, and aspects of the neurochemical identities of infracortical white matter neurons, also termed white matter interstitial cells (WMICs), in the brains of a southern lesser galago (Galago moholi), a black-capped squirrel monkey (Saimiri boliviensis boliviensis), and a crested macaque (Macaca nigra). Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most dense close to inner cortical border, decreasing in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed estimates of approximately 1.1, 10.8, and 37.7 million WMICs within the infracortical white matter of the galago, squirrel monkey, and crested macaque, respectively. The total numbers of WMICs form a distinct negative allometric relationship with brain mass and white matter volume when examined in a larger sample of primates where similar measures have been obtained. In all three primates studied, the highest densities of WMICs were in the white matter of the frontal lobe, with the occipital lobe having the lowest. Immunostaining revealed significant subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS) and calretinin, with very few WMICs containing parvalbumin, and none containing calbindin. The nNOS and calretinin immunopositive WMICs represent approximately 21% of the total WMIC population; however, variances in the proportions of these neurochemical phenotypes were noted. Our results indicate that both the squirrel monkey and crested macaque might be informative animal models for the study of WMICs in neurodegenerative and psychiatric disorders in humans.

Themes of advanced information processing in the primate brain.

Here is a review of several empirical examples of information processing that occur in the primate cerebral cortex. These include visual processing, object identification and perception, information encoding, and memory. Also, there is a discussion of the higher scale neural organization, mainly theoretical, which suggests hypotheses on how the brain internally represents objects. Altogether they support the general attributes of the mechanisms of brain computation, such as efficiency, resiliency, data compression, and a modularization of neural function and their pathways. Moreover, the specific neural encoding schemes are expectedly stochastic, abstract and not easily decoded by theoretical or empirical approaches.

The human connectome from an evolutionary perspective.

The connectome describes the comprehensive set of neuronal connections of a species' central nervous system. Identifying the network characteristics of the human macroscale connectome and comparing these features with connectomes of other species provides insight into the evolution of human brain connectivity and its role in brain function. Several network properties of the human connectome are conserved across species, with emerging evidence also indicating potential human-specific adaptations of connectome topology. This review describes the human macroscale structural and functional connectome, focusing on common themes of brain wiring in the animal kingdom and network adaptations that may underlie human brain function. Evidence is drawn from comparative studies across a wide range of animal species, and from research comparing human brain wiring with that of non-human primates. Approaching the human connectome from a comparative perspective paves the way for network-level insights into the evolution of human brain structure and function.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in a lar gibbon (Hylobates lar) brain.

We examined the number, distribution, and immunoreactivity of the infracortical white matter neuronal population, also termed white matter interstitial cells (WMICs), in the brain of a lesser ape, the lar gibbon. Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most numerous and dense close to cortical layer VI, decreasing significantly in density with depth in the white matter. Stereological analysis of NeuN-immunopositive cells revealed a global estimate of ~67.5 million WMICs within the infracortical white matter of the gibbon brain, indicating that the WMICs are a numerically significant population, ~2.5% of the total cortical gray matter neurons that would be estimated for a primate brain the mass of that of the lar gibbon. Immunostaining revealed subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS, ~7 million in number, with both small and large soma volumes), calretinin (~8.6 million in number, all of similar soma volume), very few WMICs containing parvalbumin, and no calbindin-immunopositive neurons. These nNOS, calretinin, and parvalbumin immunopositive WMICs, presumably all inhibitory neurons, represent ~23.1% of the total WMIC population. As the white matter is affected in many cognitive conditions, such as schizophrenia, autism and also in neurodegenerative diseases, understanding these neurons across species is important for the translation of findings of neural dysfunction in animal models to humans. Furthermore, studies of WMICs in species such as apes provide a crucial phylogenetic context for understanding the evolution of these cell types in the human brain.

Mammalian brain development and our grandmothering life history.

Among mammals, including humans, adult brain size and the relative size of brain components depend precisely on the duration of a highly regular process of neural development. Much wider variation is seen in rates of body growth and the state of neural maturation at life history events like birth and weaning. Large brains result from slow maturation, which in humans is accompanied by weaning early with respect to both neural maturation and longevity. The grandmother hypothesis proposes this distinctive combination of life history features evolved as ancestral populations began to depend on foods that just weaned juveniles couldn't handle. Here we trace possible reciprocal connections between brain development and life history, highlighting the resulting extended neural plasticity in a wider cognitive ecology of allomaternal care that distinguishes human ontogeny with consequences for other peculiarities of our lineage.