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Comparative studies of brain developmental timing and progression using 3D stem cell models https://doi.org/10.17863/CAM.126540 Lloyd-Davies Sánchez, Daniel Lancaster, Madeline The human brain is three times larger than those of our closest evolutionary relatives such as chimpanzees and gorillas, yet the mechanisms by which this increase in size has been achieved, and also the implications of this on human brain function and capabilities, remain largely yet to be elucidated. However, practical and ethical restrictions on great ape and human research mean that these phenomena cannot be directly studied with current modern technologies or interventions. We used self-organising brain organoid models, derived from stem cells of different relevant species to establish paradigms for comparative studies in brain development, and understand aspects of human specific brain development in vitro. In order to make fair comparisons between brain organoids of different species, we first establish a paradigm for being able to stage match brain organoids of different origins with potentially different developmental tempos, and also provide evidence that the self-organising nature of differentiation under the protocol means that developmental timings are cell line intrinsic and largely unconfounded by species-specific adaptations to the protocol timing. By generating mosaic organoids containing cells of both human and chimpanzee origin, we follow cell morphological changes and provide evidence that species-specific timings of differentiation, specifically the neuroepithelial to radial glial transition, are cell intrinsic. To disentangle whether human and chimpanzee timing differences in this transition are due to cis or trans acting genetic regulators, we generate tetraploid and hybrid cells lines and provide phenotypic and transcriptomic data pertaining to the nature of its regulation. We show that mouse derived brain organoids differentiate at an increased developmental rate compared to human brain organoids, and establish them an effective model for trialling and testing experiments on organoids, particularly relating to electrophysiology where they are able to recapitulate aspects of in-vivo and primary mouse brain samples. We provide evidence of differing developmental rates between species, using acute electrophysiological readouts from brain organoid slice cultures on high density multi-electrode arrays. We develop and design technologies for longitudinal recording of brain organoids in-situ at the airliquid interface, and provide the first evidence of circadian rhythmicity to electrophysiological activity in brain organoids. We show that normal brain organoid development is largely unperturbed in conjunction with our technology, and discuss how these electrophysiological data can be used to study brain development, and differences in species-specific developmental timings. University of Cambridge 2024-09-30 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/397387 embargo 2027-02-10 https://www.repository.cam.ac.uk/bitstreams/02fc5964-eb38-493f-b839-3e8d0248df6c/download 870e11e3f5c0e74904713380bec9a0b2 https://www.repository.cam.ac.uk/bitstreams/1eb0cf8d-8d4d-44a2-a229-d9a62fd9f6d3/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved brain evolution brain size human Homo sapiens ape chimpanzee gorilla mouse electrophysiology neuron action potential evo devo organoid stem cell development