Reverse engineering human brain evolution using organoid models

Mostajo-Radji, Mohammed A.; Schmitz, Matthew T.; Torres-Montoya, Sebastian; Pollen, Alex A.

doi:10.1016/j.brainres.2019.146582

Cited by 29 publications

(36 citation statements)

References 229 publications

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“…These data demonstrate the importance of interneurons in plasticity and complex network function. Interestingly, evolutionary studies have shown that the amount of interneurons in primates is much higher than rodents (40% vs 20% of cortical neurons respectively, see review) 31 . LTP is a typical electrophysiological feature of plasticity, which is observed in the hippocampus and is the underlying mechanism for learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

et al. 2020

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Brain organoids are promising tools for disease modeling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here, we report the directed self-organization of human induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network at a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons with supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed GABA polarity switch and reduced GDPs in >40 day BENO indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months and evidence for long-term potentiation. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modeling of disease.

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Section: Discussionmentioning

confidence: 99%

Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

et al. 2020

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“…Naturally, the functional effects of these divergent developmental profiles for the cerebellum, striatum, and prenatal thalamus remain to be understood. But the fact that prenatal stages are key holds the promise of using brain organoid technology to probe the nature of these differences, since such in vitro techniques best track these earliest developmental windows [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

A distinct brain expression profile for genes within large introgression deserts and under positive selection inHomo sapiens

Buisan

Moriano

Andirkó

et al. 2021

Preprint

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Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of `archaic' haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, and especially the cerebellum and the striatum at prenatal stages, show the most divergent transcriptomic profiles when considering genes under positive selection within introgression deserts.

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“…Our data contained overall fewer CpGs than a comparative study of the prefrontal cortex in primates using whole genome bisulfite sequencing (WGBS) [15] such that none of the genomic ranges of DMRs identified in that study were represented in our data by enough CpGs (5) to comprise a DMR. We nevertheless found the genomic ranges of the previous study's human-specific DMRs to be enriched for individual, human-specific differentially methylated CpGs in our datasets for both brain structures (Fisher's exact test, p < 0.001), with slightly over half the CpGs present in each dataset falling within these ranges showing human-specific methylation.…”

Section: Plos Geneticsmentioning

confidence: 96%

“…Humans' remarkable cognitive abilities-enabling language use, complex technology, and cultural behavior-are hallmarks of our species. The neurobiological underpinning of these traits originate in large part from developmentally established species-specific spatial and temporal patterns of gene regulation in the brain [1][2][3][4][5][6]. One important gene regulatory mechanism critical to establishing species-typical and cell type-specific transcriptional profiles is CpG methylation.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis reveals distinctive epigenetic features of the human cerebellum

et al. 2021

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Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees (Pan troglodytes) and rhesus macaques (Macaca mulatta). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution.

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Reverse engineering human brain evolution using organoid models

Cited by 29 publications

References 229 publications

Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

Developmental GABA polarity switch and neuronal plasticity in Bioengineered Neuronal Organoids

A distinct brain expression profile for genes within large introgression deserts and under positive selection inHomo sapiens

Comparative analysis reveals distinctive epigenetic features of the human cerebellum

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