Mazzocchi, L. | bioRxiv Science

bioRxiv2023

Virtual brain simulations reveal network-specific parameters in neurodegenerative dementias

IntroductionNeural circuit alterations lay at the core of brain physiopathology, and yet are hard to unveil in living subjects. Virtual brain modelling (TVB), by exploiting structural and functional MRI, yields mesoscopic parameters of connectivity and synaptic transmission. MethodsWe used TVB to simulate brain networks, which are key for human brain function, in Alzheimers disease (AD) and Frontotemporal Dementia (FTD) patients, whose connectivity and synaptic parameters remain largely unknown; we then compared them to healthy controls, to reveal novel in vivo pathological hallmarks. ResultsThe pattern of simulated parameter differed between AD and FTD, shedding light on disease-specific alterations in brain networks. Individual subjects displayed subtle differences in network parameter patterns that significantly correlated with their individual neuropsychological, clinical, and pharmacological profiles. DiscussionThese TVB simulations, by informing about a new personalized set of networks parameters, open new perspectives for understanding dementias mechanisms and design personalized therapeutic approaches.

neuroscience↗

bioRxiv2022

An essential function for autocrine Hedgehog signaling in epithelial proliferation and differentiation in the trachea

The tracheal epithelium is a primary target for pulmonary diseases as it provides a conduit for air flow between the environment and the lung lobes. The cellular and molecular mechanisms underlying airway epithelial cell proliferation and differentiation remain poorly understood. Hedgehog (Hh) signaling orchestrates communication between epithelial and mesenchymal cells in the lung, where it modulates stromal cell proliferation, differentiation and signaling back to the epithelium. Here, we reveal a new, autocrine function of Hh signaling in airway epithelial cells. Epithelial cell depletion of the ligand Sonic hedgehog (SHH) or its effector Smoothened (SMO) causes defects in both epithelial cell proliferation and differentiation. In cultured primary human airway epithelial cells, Hh signaling inhibition also hampers cell proliferation and differentiation. Epithelial Hh function is mediated, at least in part, through transcriptional activation as Hh signaling inhibition leads to downregulation of cell-type specific transcription factor genes in both the mouse trachea and human airway epithelial cells. These results provide new insights into the role of Hh signaling in epithelial cell proliferation and differentiation during airway development.

developmental biology↗