Longitudinal, in-vivo functional and molecular imaging to characterize neurodevelopment from infantile to adult age in healthy mice.

Neurodevelopmental disorders (NDDs) result from disturbances in central nervous system development. Functional and molecular imaging of rodent models provides a way to study neurodevelopment in a non-invasive, longitudinal, and quantifiable manner. Here, we present the first small-animal imaging study documenting healthy neurodevelopment at different developmental stages (infancy, adolescence, and adulthood).

Healthy 129/Sv mice were imaged at postnatal day (P)14-P20 (infant), P35-40 (juvenile), and P90-100 (adult), using resting-state functional MRI (rs-fMRI, n=13) to assess functional connectivity (FC) and dynamic 60-min [18F]SynVesT-1 PET imaging (n=12) to visualize synaptic vesicle glycoprotein 2A (SV2A) uptake as marker of synaptic density. During rs-fMRI, mice were anaesthetized with 0.4% isoflurane (ISO) and 0.1 ml/kg/h medetomidine hydrochloride. Independent component analysis (ICA) and region of interest (ROI)-based analysis of FC were performed for each timepoint. During PET imaging, mice were anesthetized with 1.5-2.5% ISO. Volume of radioligand distribution was measured semi- and quantitatively using an image-derived input function [1].

We demonstrated that both rs-fMRI and [18F]SynVesT-1 PET imaging can be performed in infant mice starting from P15. ICA-analysis of rs-fMRI data showed the presence of the Default Mode-Like Network (DMLN) at all three developmental stages. Comparison of FC between selected ROIs across ages revealed significantly increased average FC between regions of multiple networks in adults compared to infants, in particular the visual and auditory cortices, as well as between cingulate and retrosplenial and entorhinal cortices belonging to the DMLN. SV2A uptake was significantly higher at infantile than at juvenile age in all brain regions, reflecting synaptic pruning.

This study showed that small-animal rs-fMRI and [18F]SynVesT-1 PET studies are feasible starting from P15 and are promising tools to study normal neurodevelopment in rodent models across developmental stages. Similar to the human situation [2,3], we observed an increase in FC despite a reduction in synaptic density during normal rodent neurodevelopment. Future studies should confirm the utility of rs-fMRI and [18F]SynVesT-1 PET to study disease mechanisms and treatment response in rodent models of NDDs.

[1]Bertoglio et al, doi:10.1177/0271678X221101648
[2]Gao et al, doi:10.1073/pnas.0811221106
[3]Herschkowitz et al. doi:10.1055/s-2007-973720

Authors

Charissa Millevert(1,2,3), Nicholas Vidas-Guscic(1,4), Mohit H. Adhikari(1,4), Judith R. A. van Rooij(1,4), Liesbeth Vanherp(1), Elisabeth Jonckers(1,4), Steven Staelens(1,5), Daniele Bertoglio(1,4,5), Marleen Verhoye(1,4), Sarah Weckhuysen(1,2,3)

Organisations

µNEURO Research Centre of Excellence, University of Antwerp(1), Applied & Translational Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology(2), Dept. of Neurology, University Hospital Antwerp(3), Bio-Imaging Lab, MICA-BIL Core Facility, University of Antwerp(4), Molecular Imaging Center Antwerp (MICA), MICA-BIL Core Facility, University of Antwerp(5)