Tracking brain maturation in vivo: functional connectivity, white matter integrity, and synaptic density in developing mice

Abstract

Background: Investigating dynamic changes during normal brain development is essential for understanding neurodevelopmental disorders (NDDs) and assessing the impact of novel therapies for these conditions. Rodent models, with their shorter developmental timeline, offer a valuable alternative to humans. This study aimed to characterise brain maturation in mice using a longitudinal, multimodal imaging approach.

Methods: We conducted an in vivo imaging study on 31129/Sv mice with a complete longitudinal dataset available for 22 mice. Resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and [¹⁸F]SynVesT-1 PET were used to examine the development of brain functional connectivity (FC), white matter integrity, and synaptic density at three developmental stages: infancy (P14-21), juvenile (P32-42), and adulthood (P87-106).

Findings: From infancy to juvenile age, we observed a significant decrease in FC and synaptic density, alongside increases in fractional anisotropy (FA) and decreases in mean, axial, and radial diffusivity (RD). From juvenile to adult age, synaptic density and FC stabilised, while FA further increased, and RD continued to decrease. The default mode like network was identifiable in mice across all developmental stages.

Interpretation: Our findings mirror established patterns of human brain development, with infant mice allowing us to capture critical brain developmental changes, underscoring the translational relevance of our findings. This study provides a robust framework for normal rodent neurodevelopment and establishes a foundation for future research on NDDs in mice and the impact of novel treatments on neurodevelopment.

Funding: Supported by the University of Antwerp, Fonds Wetenschappelijk Onderzoek (FWO), the Queen Elisabeth Medical Foundation, the European Joint Programme on Rare Disease, and Fondation Lejeune.

Keywords: Diffusion tensor imaging; Neurodevelopment; Positron emission tomography; Resting-state functional magnetic resonance imaging; SV2A.