Changing the tempo of neuronal development to modulate neural circuit function and plasticity

The timing of neuronal development is highly variable depending on the cell type or species.

In particular human cortical neurons display a considerably protracted tempo of development, at the basis of human brain neoteny.

The mechanisms underlying neuronal neoteny start to be unravelled, but their significance for brain function and plasticity remain poorly known, despite their implications for brain diseases and repair.

This project will combine innovative technologies developed by the applicant and the host lab, including brain transplantation, molecular manipulation of developmental tempo, and neural connectivity.

Taking advantage of recent findings of the host lab that link metabolism to neuronal maturation speed, we will manipulate mitochondrial function to accelerate the maturation of human neurons in a xenotransplanted mouse model, and conversely, to decelerate murine neurons within the mouse visual cortex.

We will thus examine how increasing or decreasing neuronal maturation rates influence functional development, synaptic functions, and experience-dependent plasticity, across time and species.

Using advanced techniques including electrophysiology, in vivo calcium imaging, and monocular deprivation neural plasticity paradigms, we will explore the impact of neuronal developmental tempo on cortical circuit function and plasticity.

Finally and most excitingly we will use the same paradigms to investigate whether transplanted juvenile neurons can induce plasticity in the neuronal networks of the adult host brain.

Additionally, chemogenetic and transsynaptic tracing approaches will dissect potential mechanisms underlying the observed effects. Using MERFISH spatial transcriptomics, we aim to unveil molecular programs driving plasticity induction.

This project holds significant potential to reshape our understanding brain development and plasticity, and its implications for neurodevelopmental diseases and therapeutic interventions in the ageing brain.