Deformation-based Morphometry MRI Reveals Brain Structural Modifications in Living Mu Opioid Receptor Knockout Mice

Abstract

Mu opioid receptor (MOR) activation facilitates reward processing and reduces pain, and brain networks underlying these effects are under intense investigation. Mice lacking the MOR gene (MOR KO mice) show lower drug and social reward, enhanced pain sensitivity and altered emotional responses. Our previous neuroimaging analysis using Resting-state (Rs) functional Magnetic Resonance Imaging (fMRI) showed significant alterations of functional connectivity (FC) within reward/aversion networks in these mice, in agreement with their behavioral deficits. Here we further used a structural MRI approach to determine whether volumetric alterations also occur in MOR KO mice. We acquired anatomical images using a 7-Tesla MRI scanner and measured deformation-based morphometry (DBM) for each voxel in subjects from MOR KO and control groups. Our analysis shows marked anatomical differences in mutant animals. We observed both local volumetric contraction (striatum, nucleus accumbens, bed nucleus of the stria terminalis, hippocampus, hypothalamus and periacqueducal gray) and expansion (prefrontal cortex, amygdala, habenula, and periacqueducal gray) at voxel level. Volumetric modifications occurred mainly in MOR-enriched regions and across reward/aversion centers, consistent with our prior FC findings. Specifically, several regions with volume differences corresponded to components showing highest FC changes in our previous Rs-fMRI study, suggesting a possible function-structure relationship in MOR KO-related brain differences. In conclusion, both Rs-fMRI and volumetric MRI in live MOR KO mice concur to disclose functional and structural whole-brain level mechanisms that likely drive MOR-controlled behaviors in animals, and may translate to MOR-associated endophenotypes or disease in humans.