Modellazione dell'attività delle reti neuronali precoci con organoidi cerebrali per lo studio dei disturbi del neurosviluppo

Organoids are emerging as a powerful tool for modeling human brain development and neurological diseases. Thanks to their ability to recapitulate, with good approximation, the cellular and molecular characteristics of brain development that would otherwise be inaccessible, they can be used to study the effects of mutations on the developmental trajectories of different brain regions. This thesis aims to argue, through the analysis of three different experimental works, for the use of telencephalic organoids as a model for studying the establishment of the first spontaneous electrical interactions during the embryonic development of the human brain. Specifically, Trujillo et al. demonstrated that the emergence of network activity and its transition to a more complex pattern of activity strictly depends on the composition of the organoid itself, which consistently changes in long-term cultures. Interestingly, network-level events (i.e., oscillations) were shown to be similar to the EEG features of human preterm neonates. Samarasinghe et al. upgraded the model by combining organoids specified as cortical and ganglionic eminence, respectively. The enrichment in GABAergic inhibitory cells at the level of the cortical compartments, in the so-called assembloid, consistently improved the complexity of the recorded electrical patterns and enabled the modeling of the neurodevelopmental condition Rett syndrome and its electrical alterations. Finally, Osaki et al. presented a new organoid-based model consisting of two cortical organoids connected through an axon bundle, recapitulating the callosal projection. This type of inter-regional connection boosted the functionality of the organoid circuit demonstrating that bidirectional axonal connections, should be implemented in this type of models to enhance their functional resemblance to the human brain. The development of these models is particularly relevant for furthering our understanding of the mechanisms behind the emergence of spontaneous electrical activity patterns and their influence on brain development. Moreover, the upgrading of this in vitro model will allow for future studies aimed at detecting early electrophysiological biomarkers for the early diagnosis of neuropsychiatric conditions and finding potential personalized therapeutic options.