Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

Significance Mice manipulated by targeted deletion of a specific brain gene show diverse pathological phenotypes, apparent, for example, in behavioral experiments. To explain observed findings, connectome genetics attempts to uncover how brain functional connectivity is affected by genetics. However the causal impact of a single gene on whole-brain networks is still unclear. Here the sole targeted deletion of the mu opioid receptor gene (Oprm1), the main target for morphine, induced widespread remodeling of brain functional connectome in mice. The strongest perturbations occurred within the so-called reward/aversion-circuitry, predominantly influencing the negative affect centers. We present a hypothesis-free analysis of combined structural and functional connectivity data obtained via MRI of the living mouse brain, and identify a specific Oprm1 gene-to-network signature. Connectome genetics seeks to uncover how genetic factors shape brain functional connectivity; however, the causal impact of a single gene’s activity on whole-brain networks remains unknown. We tested whether the sole targeted deletion of the mu opioid receptor gene (Oprm1) alters the brain connectome in living mice. Hypothesis-free analysis of combined resting-state fMRI diffusion tractography showed pronounced modifications of functional connectivity with only minor changes in structural pathways. Fine-grained resting-state fMRI mapping, graph theory, and intergroup comparison revealed Oprm1-specific hubs and captured a unique Oprm1 gene-to-network signature. Strongest perturbations occurred in connectional patterns of pain/aversion-related nodes, including the mu receptor-enriched habenula node. Our data demonstrate that the main receptor for morphine predominantly shapes the so-called reward/aversion circuitry, with major influence on negative affect centers.