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Gray matter cortical thickness varies with brain regions and phylogeny. (A) Twelve brain region volumes and GM thickness presented in a pie-chart matrix of positive (blue gradient) and negative (red gradient) correlations. Note that all brain region volumes - except BBO, which is a developmentally and functionally separate region - show very high (R² > 0.8) positive correlations, whereas cortical thickness is lowly (R² < 0.4) correlated with all brain region volumes. BBO, olfactory bulb; CRB, cerebellum; CT, cortical thickness; DCP, diencephalon; HPC, hippocampus; LBP, piriform lobe; MCP, mesencephalon; MDO, medulla oblongata; NHP, neurohypophysis; NPL, neopallial; SPM, septum; STM, striatum; TCP, telencephalon. Volumetric data from Stephan et al. (1981). (B) GM thickness is measured as the average distance between layers I and VI (yellow bars) in a systematic random sample of the neocortex. (C) A phylogenetic tree of 40 mammal species (Bininda-Emonds et al. 2007) showing the distribution of brain weight (log10 + 1) and GM thickness (log10 + 1) across species. GM thickness in all species was measured with Fiji (Schindelin et al., 2012) on slides from brainmuseum.org. See Lewitus et al. (2013) and Table A1 for neuroanatomical data in (C).
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There is a basic rule to mammalian neocortical expansion: as it expands, so does it fold. The degree to which it folds, however, cannot strictly be attributed to its expansion. Across species, cortical volume does not keep pace with cortical surface area, but rather folds appear more rapidly than expected. As a result, larger brains quickly become...
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... 140 This also seems to be the case in neurons, as demonstrated in a mouse study showing that, partly facilitated by MCT8, TH can act in these cells, entering hidden inside endosomes that act akin to a Trojan horse-protecting TH from degradation from the axonal termini to the nucleus. 81 Due to the altered T3 transport, MCT8-deficient brain organoids exhibit altered neurogenesis, 141 pointing to an MCT8-mediated TH transport into the neural precursor cells (the source of most human cortical neurons 142 ) that can trigger developmental programs in these cells. 143 This is supported by the fact that MCT8 is expressed in neural precursor cells in fetal brains and brain organoids. ...
Background: Normal brain development, mood, and cognitive functions depend on thyroid hormone (TH) action. However, little is known about how TH mediates its actions in the human brain. This is because of limited access to human brains deprived of TH during fetal and early postnatal life, as well as from adults with altered thyroid status. One way to partially bypass these limitations is by using magnetic resonance imaging and spectroscopy, two neuroimaging techniques that provide detailed, non-invasive information on human brain structure and function. Another way is using human-induced pluripotent stem cells (hiPSCs)-derived three-dimensional in vitro systems, known as brain organoids, which allow for studying fundamental aspects of the early stages of human brain development.
Summary: This narrative review focuses on neuroimaging and brain organoid studies. Neuroimaging of human brains performed in individuals with different thyroid conditions provides information on the volume, myelination, blood flow, neural activity, and connectivity of different areas. Such studies show that a suboptimal thyroid status can impact human brain development and its normal function throughout life. This is true not only for patients with sporadic congenital hypothyroidism, during pregnancy or early after birth, but also for adult patients with hypo- or hyperthyroidism and for patients carrying mutations that manifest as impaired sensitivity to TH–and even for normal individuals during aging. Studies using brain organoids generated from iPSCs of healthy individuals or patients with thyroid genetic conditions provide insights into how TH can impact the early development of the human cerebral cortex.
Conclusions: The developmental alterations in children born to mothers with different degrees of gestational hypothyroidism or who developed hypothyroidism early in life are remarkable, affecting multiple brain regions and pathways, including the cerebral cortex, hippocampus, cerebellum, interhemispheric and corticospinal tracts, and associative nuclei. The data connecting such changes to poor neurological outcomes in adult patients with hypothyroidism represent an objective link between thyroid-specific functional brain alterations and behavior. Growing brain organoids require TH, proving critical for human neuro- and oligodendrogenesis. These models proved useful in screening drugs with potential therapeutics for patients with genetic thyroid diseases.
... The resulting buildup of T3 can trigger developmental programs in these cells. The relevance of this observation cannot be underestimated, as these neural precursor cells are the source of most human cortical neurons (78). Further research into the role of MCT8 and D2 in the biology of these cells is in progress. ...
Patients with mutations in the thyroid hormone (TH) cell transporter MCT8 gene develop severe neuropsychomotor retardation known as the Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human iPSCs from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired T3 transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3-inducibility of TH-regulated genes. In contrast, the TH-analogs 3,5-diiodothyropropionic acid and 3,3’,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof-of-concept that lack of T3 transport underlies the pathophysiology of AHDS, and demonstrating the clinical potential for TH analogs to be used in treating AHDS patients. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for AHDS patients.
... Several studies show a strong association between BP enrichment and increases in the propensity of the cortex to convolute [79][80][81][82][83][84][85][86]. As a regulator of neural progenitor cell multipotency, proliferation, and differentiation in the central nervous system, the transcription factor Pax6 is recognized as a key player in the expansion of the neurogenic progenitor pool and, hence, neurogenesis. ...
Enrichment of basal progenitors (BPs) in the developing neocortex is a central driver of cortical enlargement. The transcription factor Pax6 is known as an essential regulator in generation of BPs. H3 lysine 9 acetylation (H3K9ac) has emerged as a crucial epigenetic mechanism that activates the gene expression program required for BP pool amplification. In this current work, we applied immunohistochemistry, RNA sequencing, chromatin immunoprecipitation and sequencing, and the yeast two-hybrid assay to reveal that the BP-genic effect of H3 acetylation is dependent on Pax6 functionality in the developing mouse cortex. In the presence of Pax6, increased H3 acetylation caused BP pool expansion, leading to enhanced neurogenesis, which evoked expansion and quasi-convolution of the mouse neocortex. Interestingly, H3 acetylation activation exacerbates the BP depletion and corticogenesis reduction effect of Pax6 ablation in cortex-specific Pax6 mutants. Furthermore, we found that H3K9 acetyltransferase KAT2A/GCN5 interacts with Pax6 and potentiates Pax6-dependent transcriptional activity. This explains a genome-wide lack of H3K9ac, especially in the promoter regions of BP-genic genes, in the Pax6 mutant cortex. Together, these findings reveal a mechanistic coupling of H3 acetylation and Pax6 in orchestrating BP production and cortical expansion through the promotion of a BP gene expression program during cortical development.
... A type of highly neurogenic progenitors, the basal radial glial cells (bRGCs), were found to be abundant in the gyrencephalic species, such as the human brain ( Figure 2). bRGCS are thought to be important for the dramatic expansion of cortical neuronal population and the gyrification (the folds at the brain surface) of the human brain [27][28][29]. In lissencephalic species, such as rodents, these cells are much fewer and has only limited neurogenic potential [30]. ...
The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.
... Human iPSCsderived microglial have been cultured along with brain organoids and shown to adhere to, and migrate into the interior of the brain organoid [108]. Other challenges include obstacles to spatial organization, complexity, maturation, appropriate cortical folding, and gyrification as observed in gyrencephalic mammals [109,110]. The lack of appropriate cortical folding in the brain organoids could result from the fact that the cultures do not reach a developmental stage, at which gyrification is present [110]. ...
... Other challenges include obstacles to spatial organization, complexity, maturation, appropriate cortical folding, and gyrification as observed in gyrencephalic mammals [109,110]. The lack of appropriate cortical folding in the brain organoids could result from the fact that the cultures do not reach a developmental stage, at which gyrification is present [110]. There have been attempts to generate a 'pseudo folding' into brain organoids by inducing neural progenitor cells (NPC) overgrowth via knockout PTEN or by microchips [111,112]. ...
Our current knowledge regarding the development of the human brain mostly derives from experimental studies on non-human primates, sheep, and rodents. However, these studies may not completely simulate all the features of human brain development as a result of species differences and variations in pre- and postnatal brain maturation. Therefore, it is important to supplement the in vivo animal models to increase the possibility that preclinical studies have appropriate relevance for potential future human trials. Three-dimensional brain organoid culture technology could complement in vivo animal studies to enhance the translatability of the preclinical animal studies and the understanding of brain-related disorders. In this review, we focus on the development of a model of hypoxic-ischemic (HI) brain injury using human brain organoids to complement the translation from animal experiments to human pathophysiology. We also discuss how the development of these tools provides potential opportunities to study fundamental aspects of the pathophysiology of HI-related brain injury including differences in the responses between males and females.
... Therefore, even though at first, these different fields were brought together mainly to validate or invalidate a given model based on its compatibility with the other fields, it appears that the mechanisms are not only concurrent but also interactive, and recent reviews advocate the combination of the three domains to understand the complex mechanisms at play. Among them, some have focused on the combination of cellular biology and biomechanics (Lewitus et al., 2013;Ronan and Fletcher, 2015;Striedter et al., 2015), including a dual perspective review with both a cellular biology (Borrell, 2018) and a biomechanistic (Kroenke and Bayly, 2018) point of view, with comments from the other perspective. Others have rather focused on the combination between cellular biology and genetic processes, which seem to orchestrate the biological events leading to cortical folding (Sur and Rubenstein, 2005). ...
The folding of the human brain mostly takes place in utero, making it challenging to study. After a few pioneer studies looking into it in post-mortem foetal specimen, modern approaches based on neuroimaging have allowed the community to investigate the folding process in vivo, its normal progression, its early disturbances, and its relationship to later functional outcomes. In this review article, we aimed to first give an overview of the current hypotheses on the mechanisms governing cortical folding. After describing the methodological difficulties raised by its study in fetuses, neonates and infants with magnetic resonance imaging (MRI), we reported our current understanding of sulcal pattern emergence in the developing brain. We then highlighted the functional relevance of early sulcal development, through recent insights about hemispheric asymmetries and early factors influencing this dynamic such as prematurity. Finally, we outlined how longitudinal studies have started to relate early folding markers and the child's sensorimotor and cognitive outcome. Through this review, we hope to raise awareness on the potential of studying early sulcal patterns both from a fundamental and clinical perspective, as a window into early neurodevelopment and plasticity in relation to growth in utero and postnatal environment of the child.
... Brain size and cortical folding show extensive variation across mammals, including recurrent independent increases and decreases (Montgomery et al., 2016;Boddy et al., 2012;Lewitus et al., 2013;Smaers et al., 2021). For example, most rodents have a small brain and an unfolded cortex , while carnivores, cetaceans, and primates generally have enlarged and folded cortices, peaking in dolphin and human. ...
Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it controls proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay and identify one CRE that likely co-evolves with cortical folding in Old World monkeys and apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species.
... In gyrencephalic species (e.g., human, macaque, ferret) the SVZ is vastly expanded and subdivided into the inner SVZ (iSVC) and outer SVZ (oSVZ). oRG primarily populate the oSVZ and oRG are largely absent in the developing cerebral cortex of lissencephalic species (e.g., mouse, rat, rabbit), linking the expansion of this compartment to neocortical expansion and folding (Lewitus et al., 2013;Reillo et al., 2011;Sun and Hevner, 2014). ...
Mammalian outer radial glia (oRG) emerge as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. The in vitro generation of oRG is essential to model and investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such as GFAP, LIFR, HOPX, which closely matches human oRG in vivo. In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell-types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.
... All these data can be integrated under the umbrella of the human brain evolution hypotheses that postulate that the larger human neocortex could arise from an increasing number of cortical neurons generated in the germinal zones during foetal development [35,37,105,106]. This neocortical expansion would be driven by a greater and prolonged proliferative capacity rather than due to the differentiation capacity of the human neural stem and progenitor cells, which are differences indicative of a species-specific transcriptomic regulation of neocortex development [37,107]. In this sense, findings regarding the interaction between HARs and genes that are related to neuronal differentiation and proliferation-such as PTBP2 or PPP1R17 [52,60]-together with the specific enrichment of HAR genes in radial glia during neurodevelopment [58], are highly relevant. ...
Schizophrenia is a psychiatric disorder that results from genetic and environmental factors interacting and disrupting neurodevelopmental trajectories. Human Accelerated Regions (HARs) are evolutionarily conserved genomic regions that have accumulated human-specific sequence changes. Thus, studies on the impact of HARs in the context of neurodevelopment, as well as with respect to adult brain phenotypes, have increased considerably in the last few years. Through a systematic approach, we aim to offer a comprehensive review of HARs’ role in terms of human brain development, configuration, and cognitive abilities, as well as whether HARs modulate the susceptibility to neurodevelopmental psychiatric disorders such as schizophrenia. First, the evidence in this review highlights HARs’ molecular functions in the context of the neurodevelopmental regulatory genetic machinery. Second, brain phenotypic analyses indicate that HAR genes’ expression spatially correlates with the regions that suffered human-specific cortical expansion, as well as with the regional interactions for synergistic information processing. Lastly, studies based on candidate HAR genes and the global “HARome” variability describe the involvement of these regions in the genetic background of schizophrenia, but also in other neurodevelopmental psychiatric disorders. Overall, the data considered in this review emphasise the crucial role of HARs in human-specific neurodevelopment processes and encourage future research on this evolutionary marker for a better understanding of the genetic basis of schizophrenia and other neurodevelopmental-related psychiatric disorders. Accordingly, HARs emerge as interesting genomic regions that require further study in order to bridge the neurodevelopmental and evolutionary hypotheses in schizophrenia and other related disorders and phenotypes.
... Regional variations to cytoarchitecture are, in part, rooted in neurodevelopment (1,18,20,(26)(27)(28)(29)(30). During prenatal development, differences in the developmental timing of neurogenesis lead to highly eulaminate regions-such as the primary visual cortex-developing more slowly than agranular regions (31), suggesting that prenatal development lays the foundation for the S-F axis. ...
Cortical variations in cytoarchitecture form a sensory-fugal axis that shapes regional profiles of extrinsic connectivity and is thought to guide signal propagation and integration across the cortical hierarchy. While neuroimaging work has shown that this axis constrains local properties of the human connectome, it remains unclear whether it also shapes the asymmetric signaling that arises from higher-order topology. Here, we used network control theory to examine the amount of energy required to propagate dynamics across the sensory-fugal axis. Our results revealed an asymmetry in this energy, indicating that bottom-up transitions were easier to complete compared to top-down. Supporting analyses demonstrated that asymmetries were underpinned by a connectome topology that is wired to support efficient bottom-up signaling. Lastly, we found that asymmetries correlated with differences in communicability and intrinsic neuronal time scales and lessened throughout youth. Our results show that cortical variation in cytoarchitecture may guide the formation of macroscopic connectome topology.
