CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.

Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function.

The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.

Thought for food: the endothermic brain hypothesis.

The evolution of whole-body endothermy occurred independently in dinosaurs and mammals and was associated with some of the most significant neurocognitive shifts in life's history. These included a 20-fold increase in neurons and the evolution of new brain structures, supporting similar functions in both lineages. We propose the endothermic brain hypothesis, which holds that elaborations in endotherm brains were geared towards increasing caloric intake through efficient foraging. The hypothesis is grounded in the intrinsic coupling of cognition and organismic self-maintenance. We argue that coevolution of increased metabolism and new forms of cognition should be jointly investigated in comparative studies of behaviors and brain anatomy, along with studies of fossil species. We suggest avenues for such research and highlight critical open questions.

A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution.

The definition of molecular and cellular mechanisms contributing to brain ontogenetic trajectories is essential to investigate the evolution of our species. Yet their functional dissection at an appropriate level of granularity remains challenging. Capitalizing on recent efforts that have extensively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework to perform trajectory inference and gene regulatory network reconstruction, (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and paleogenomic analysis for a higher-resolution mapping of derived regulatory variants in our species in comparison with our closest relatives. We provide evidence for cell type-specific regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a key role for a cholesterol program in outer radial glia, regulated by zinc-finger transcription factor KLF6. A cartography of the regulatory landscape impacted by Homo sapiens-derived variants reveals signals of selection clustering around regulatory regions associated with GLI3, a well-known regulator of radial glial cell cycle, and impacting KLF6 regulation. Our study contributes to the evidence of significant changes in metabolic pathways in recent human brain evolution.

Evolutionary and biomedical implications of sex differences in the primate brain transcriptome.

Humans exhibit sex differences in the prevalence of many neurodevelopmental disorders and neurodegenerative diseases. Here, we generated one of the largest multi-brain-region bulk transcriptional datasets for the rhesus macaque and characterized sex-biased gene expression patterns to investigate the translatability of this species for sex-biased neurological conditions. We identify patterns similar to those in humans, which are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and support the rhesus macaque model for the translational study of these conditions.

The central role of the individual in the history of brains.

Every species' brain, body and behavior is shaped by the contingencies of their evolutionary history; these exert pressures that change their developmental trajectories. There is, however, another set of contingencies that shape us and other animals: those that occur during a lifetime. In this perspective piece, we show how these two histories are intertwined by focusing on the individual. We suggest that organisms--their brains and behaviors--are not solely the developmental products of genes and neural circuitry but individual centers of action unfolding in time. To unpack this idea, we first emphasize the importance of variation and the central role of the individual in biology. We then go over "errors in time" that we often make when comparing development across species. Next, we reveal how an individual's development is a process rather than a product by presenting a set of case studies. These show developmental trajectories as emerging in the contexts of the "the actual now" and "the presence of the past". Our consideration reveals that individuals are slippery-they are never static; they are a set of on-going, creative activities. In light of this, it seems that taking individual development seriously is essential if we aspire to make meaningful comparisons of neural circuits and behavior within and across species.

Evolution of neural circuitry and cognition.

Neural circuits govern the interface between the external environment, internal cues and outwardly directed behaviours. To process multiple environmental stimuli and integrate these with internal state requires considerable neural computation. Expansion in neural network size, most readily represented by whole brain size, has historically been linked to behavioural complexity, or the predominance of cognitive behaviours. Yet, it is largely unclear which aspects of circuit variation impact variation in performance. A key question in the field of evolutionary neurobiology is therefore how neural circuits evolve to allow improved behavioural performance or innovation. We discuss this question by first exploring how volumetric changes in brain areas reflect actual neural circuit change. We explore three major axes of neural circuit evolution-replication, restructuring and reconditioning of cells and circuits-and discuss how these could relate to broader phenotypes and behavioural variation. This discussion touches on the relevant uses and limitations of volumetrics, while advocating a more circuit-based view of cognition. We then use this framework to showcase an example from the insect brain, the multi-sensory integration and internal processing that is shared between the mushroom bodies and central complex. We end by identifying future trends in this research area, which promise to advance the field of evolutionary neurobiology.

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition.

Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations' origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia-neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron-glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.

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.

Functional sensory circuits built from neurons of two species.

A central question for regenerative neuroscience is whether synthetic neural circuits, such as those built from two species, can function in an intact brain. Here, we apply blastocyst complementation to selectively build and test interspecies neural circuits. Despite approximately 10-20 million years of evolution, and prominent species differences in brain size, rat pluripotent stem cells injected into mouse blastocysts develop and persist throughout the mouse brain. Unexpectedly, the mouse niche reprograms the birth dates of rat neurons in the cortex and hippocampus, supporting rat-mouse synaptic activity. When mouse olfactory neurons are genetically silenced or killed, rat neurons restore information flow to odor processing circuits. Moreover, they rescue the primal behavior of food seeking, although less well than mouse neurons. By revealing that a mouse can sense the world using neurons from another species, we establish neural blastocyst complementation as a powerful tool to identify conserved mechanisms of brain development, plasticity, and repair.

Anatomical and volumetric description of the guiana dolphin (Sotalia guianensis) brain from an ultra-high-field magnetic resonance imaging.

The Guiana dolphin (Sotalia guianensis) is a common species along Central and South American coastal waters. Although much effort has been made to understand its behavioral ecology and evolution, very little is known about its brain. The use of ultra-high field MRI in anatomical descriptions of cetacean brains is a very promising approach that is still uncommon. In this study, we present for the first time a full anatomical description of the Guiana dolphin's brain based on high-resolution ultra-high-field magnetic resonance imaging, providing an exceptional level of brain anatomical details, and enriching our understanding of the species. Brain structures were labeled and volumetric measurements were delineated for many distinguishable structures, including the gray matter and white matter of the cerebral cortex, amygdala, hippocampus, superior and inferior colliculi, thalamus, corpus callosum, ventricles, brainstem and cerebellum. Additionally, we provide the surface anatomy of the Guiana dolphin brain, including the labeling of main sulci and gyri as well as the calculation of its gyrification index. These neuroanatomical data, absent from the literature to date, will help disentangle the history behind cetacean brain evolution and consequently, mammalian evolution, representing a significant new source for future comparative studies.

How smart was T. rex? Testing claims of exceptional cognition in dinosaurs and the application of neuron count estimates in palaeontological research.

Recent years have seen increasing scientific interest in whether neuron counts can act as correlates of diverse biological phenomena. Lately, Herculano-Houzel (2023) argued that fossil endocasts and comparative neurological data from extant sauropsids allow to reconstruct telencephalic neuron counts in Mesozoic dinosaurs and pterosaurs, which might act as proxies for behaviors and life history traits in these animals. According to this analysis, large theropods such as Tyrannosaurus rex were long-lived, exceptionally intelligent animals equipped with "macaque- or baboon-like cognition", whereas sauropods and most ornithischian dinosaurs would have displayed significantly smaller brains and an ectothermic physiology. Besides challenging established views on Mesozoic dinosaur biology, these claims raise questions on whether neuron count estimates could benefit research on fossil animals in general. Here, we address these findings by revisiting Herculano-Houzel's (2023) work, identifying several crucial shortcomings regarding analysis and interpretation. We present revised estimates of encephalization and telencephalic neuron counts in dinosaurs, which we derive from phylogenetically informed modeling and an amended dataset of endocranial measurements. For large-bodied theropods in particular, we recover significantly lower neuron counts than previously proposed. Furthermore, we review the suitability of neurological variables such as neuron numbers and relative brain size to predict cognitive complexity, metabolic rate and life history traits in dinosaurs, coming to the conclusion that they are flawed proxies for these biological phenomena. Instead of relying on such neurological estimates when reconstructing Mesozoic dinosaur biology, we argue that integrative studies are needed to approach this complex subject.

The Fractal Geometry of the Human Brain: An Evolutionary Perspective.

The evolution of the brain in mammals is characterized by changes in size, architecture, and internal organization. Consequently, the geometry of the brain, and especially the size and shape of the cerebral cortex, has changed notably during evolution. Comparative studies of the cerebral cortex suggest that there are general architectural principles governing its growth and evolutionary development. In this chapter, some of the design principles and operational modes that underlie the fractal geometry and information processing capacity of the cerebral cortex in primates, including humans, will be explored. It is shown that the development of the cortex coordinates folding with connectivity in a way that produces smaller and faster brains.

Unveiling the neuroanatomy of Josephoartigasia monesi and the evolution of encephalization in caviomorph rodents.

Caviomorph rodents are an exceptional model for studying the effects of ecological factors and size relations on brain evolution. These mammals are not only speciose and ecologically diverse but also present wide body size disparity, especially when considering their fossil relatives. Here, we described the brain anatomy of the largest known rodent, Josephoartigasia monesi, uncovering distinctive features within this species regarding other taxa. Albeit resembling extant pacarana Dinomys branickii, J. monesi stands out due to its longer olfactory tract and well-developed sagittal sinus. Challenging the previous hypothesis that giant rodents possessed comparatively smaller brains, we found that J. monesi and another giant extinct rodent, Neoepiblema acreensis, are within the encephalization range of extant caviomorphs. This was unraveled while developing the a Phylogenetic Encephalization Quotient (PEQ) for Caviomorpha. With PEQ, we were able to trace brain-size predictions more accurately, accounting for species-shared ancestry while adding the extinct taxa phenotypic diversity into the prediction model. According to our results, caviomorphs encephalization patterns are not the product of ecological adaptations, and brain allometry is highly conservative within the clade. We challenge future studies to investigate caviomorphs encephalization within different taxonomic ranks while increasing the sampled taxa diversity, especially of extinct forms, in order to fully comprehend the magnitude of this evolutionary stasis.

The partial upward migration of the laryngeal motor cortex: A window to the human brain evolution.

The pioneer cortical electrical stimulation studies of the last century did not explicitly mark the location of the human laryngeal motor cortex (LMC), but only the "vocalization area" in the lower half of the lateral motor cortex. In the final years of 2010́s, neuroimaging studies did demonstrate two human cortical laryngeal representations, located at the opposing ends of the orofacial motor zone, therefore termed dorsal (LMCd) and ventral laryngeal motor cortex (LMCv). Since then, there has been a continuing debate regarding the origin, function and evolutionary significance of these areas. The "local duplication model" posits that the LMCd evolved by a duplication of an adjacent region of the motor cortex. The "duplication and migration model" assumes that the dorsal LMCd arose by a duplication of motor regions related to vocalization, such as the ancestry LMC, followed by a migration into the orofacial region of the motor cortex. This paper reviews the basic arguments of these viewpoints and suggests a new explanation, declaring that the LMCd in man is rather induced through the division of the unitary LMC in nonhuman primates, upward shift and relocation of its motor part due to the disproportional growth of the head, face, mouth, lips, and tongue motor areas in the ventral part of the human motor homunculus. This explanation may be called "expansion-division and relocation model".

Translating the Timing of Developmental Benchmarks in Short-Tailed Opossums (Monodelphisdomestica) to Facilitate Comparisons with Commonly Used Rodent Models.

INTRODUCTION: The gray short-tailed opossum, Monodelhis domestica (M. domestica), is a widely used marsupial model species that presents unique advantages for neurodevelopmental studies. Notably their extremely altricial birth allows manipulation of postnatal pups at timepoints equivalent to embryonic stages of placental mammals. A robust literature exists on the development of short-tailed opossums, but many researchers working in the more conventional model species of mice and rats may find it daunting to identify the appropriate age at which to conduct experiments. METHODS: Here, we present detailed staging diagrams taken from photographic observations of 40 individual pups, in 6 litters, over 25 timepoints across postnatal development. We also present a comparative neurodevelopmental timeline of short-tailed opossums (M. domestica), the house mouse (Mus musculus), and the laboratory rat (Rattus norvegicus) during embryonic as well as postnatal development, using timepoints taken from this study and a review of existing literature, and use this dataset to present statistical models comparing the opossum to the rat and mouse. RESULTS: One aim of this research was to aid in testing the generalizability of results found in rodents to other mammalian brains, such as the more distantly related metatherians. However, this broad dataset also allows the identification of potential heterochronies in opossum development compared to rats and mice. In contrast to previous work, we found broad similarity between the pace of opossum neural development with that of rats and mice. We also found that development of some systems was accelerated in the opossum, such as the forelimb motor plant, oral motor control, and some aspects of the olfactory system, while the development of the cortex, some aspects of the retina, and other aspects of the olfactory system are delayed compared to the rat and mouse. DISCUSSION: The pace of opossum development is broadly similar to that of mice and rats, which underscores the usefulness of this species as a compliment to the more commonly used rodents. Many features that differ the most between opossums and rats and mice were either clustered around the day of birth and were features that have functional importance for the pup immediately after or during birth, or were features that have reduced functional importance for the pup until later in postnatal development, given that it is initially attached to the mother.

Spatio-molecular profiles shape the human cerebellar hierarchy along the sensorimotor-association axis.

Cerebellar involvement in both motor and non-motor functions manifests in specific regions of the human cerebellum, revealing the functional heterogeneity within it. One compelling theory places the heterogeneity within the cerebellar functional hierarchy along the sensorimotor-association (SA) axis. Despite extensive neuroimaging studies, evidence for the cerebellar SA axis from different modalities and scales was lacking. Thus, we establish a significant link between the cerebellar SA axis and spatio-molecular profiles. Utilizing the gene set variation analysis, we find the intermediate biological principles the significant genes leveraged to scaffold the cerebellar SA axis. Interestingly, we find these spatio-molecular profiles notably associated with neuropsychiatric dysfunction and recent evolution. Furthermore, cerebello-cerebral interactions at genetic and functional connectivity levels mirror the cerebral cortex and cerebellum's SA axis. These findings can provide a deeper understanding of how the human cerebellar SA axis is shaped and its role in transitioning from sensorimotor to association functions.

Evolution of gene expression across brain regions in behaviourally divergent deer mice.

The evolution of innate behaviours is ultimately due to genetic variation likely acting in the nervous system. Gene regulation may be particularly important because it can evolve in a modular brain-region specific fashion through the concerted action of cis- and trans-regulatory changes. Here, to investigate transcriptional variation and its regulatory basis across the brain, we perform RNA sequencing (RNA-Seq) on ten brain subregions in two sister species of deer mice (Peromyscus maniculatus and P. polionotus)-which differ in a range of innate behaviours, including their social system-and their F1 hybrids. We find that most of the variation in gene expression distinguishes subregions, followed by species. Interspecific differential expression (DE) is pervasive (52-59% of expressed genes), whereas the number of DE genes between sexes is modest overall (~3%). Interestingly, the identity of DE genes varies considerably across brain regions. Much of this modularity is due to cis-regulatory divergence, and while 43% of genes were consistently assigned to the same gene regulatory class across subregions (e.g. conserved, cis- or trans-regulatory divergence), a similar number were assigned to two or more different gene regulatory classes. Together, these results highlight the modularity of gene expression differences and divergence in the brain, which may be key to explain how the evolution of brain gene expression can contribute to the astonishing diversity of animal behaviours.

From active affordance to active inference: vertical integration of cognition in the cerebral cortex through dual subcortical control systems.

In previous papers, we proposed that the dorsal attention system's top-down control is regulated by the dorsal division of the limbic system, providing a feedforward or impulsive form of control generating expectancies during active inference. In contrast, we proposed that the ventral attention system is regulated by the ventral limbic division, regulating feedback constraints and error-correction for active inference within the neocortical hierarchy. Here, we propose that these forms of cognitive control reflect vertical integration of subcortical arousal control systems that evolved for specific forms of behavior control. The feedforward impetus to action is regulated by phasic arousal, mediated by lemnothalamic projections from the reticular activating system of the lower brainstem, and then elaborated by the hippocampus and dorsal limbic division. In contrast, feedback constraint-based on environmental requirements-is regulated by the tonic activation furnished by collothalamic projections from the midbrain arousal control centers, and then sustained and elaborated by the amygdala, basal ganglia, and ventral limbic division. In an evolutionary-developmental analysis, understanding these differing forms of active affordance-for arousal and motor control within the subcortical vertebrate neuraxis-may help explain the evolution of active inference regulating the cognition of expectancy and error-correction within the mammalian 6-layered neocortex.

Possible roles of deep cortical neurons and oligodendrocytes in the neural basis of human sociality.

Sociality is an instinctive property of organisms that live in relation to others and is a complex characteristic of higher order brain functions. However, the evolution of the human brain to acquire higher order brain functions, such as sociality, and the neural basis for executing these functions and their control mechanisms are largely unknown. Several studies have attempted to evaluate how human sociality was acquired during the course of evolution and the mechanisms controlling sociality from a neurodevelopment viewpoint. This review discusses these findings in the context of human brain evolution and the pathophysiology of autism spectrum disorder (ASD). Comparative genomic studies of postmortem primate brains have demonstrated human-specific regulatory mechanisms underlying higher order brain functions, providing evidence for the contribution of oligodendrocytes to human brain function. Functional analyses of the causative genes of ASD in animal models have demonstrated that the neural basis of social behavior is associated with layer 6 (L6) of the neocortex and oligodendrocytes. These findings demonstrate that both neurons and oligodendrocytes contribute to the neural basis and molecular mechanisms underlying human brain evolution and social functioning. This review provides novel insights into sociability and the corresponding neural bases of brain disorders and evolution.