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

Abstract

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. mouse brain connectivity | resting-state functional MRI | diffusion tensor imaging | mu opioid receptor | reward/aversion network N euronal connectivity is at the foundation of brain function (1) and the concept that brain connectivity patterns are dynamically shaped by experience, pathology, and genetics has gained increasing importance. In humans, MRI has opened the era of connectome/imaging genetics to elucidate how genetic factors affect brain organization and connectivity in healthy individuals and disease, and to correlate genotype to phenotype (2). However, the causal impact of a single gene on overall functional connectivity (FC) remains largely unknown, and animal research is best suited to this goal. Here we tested whether combined functional/structural MRI in live animals (3-8) coupled to open-ended postprocessing analysis would reveal connectivity alterations upon targeted inactivation of a single gene. The mu opioid receptor (MOR) mediates the remarkably potent analgesic and addictive properties of opiates, like morphine (9), and belongs to the endogenous opioid system that controls sensory, emotional, and cognitive processes. This receptor is broadly distributed throughout the nervous system (10). It is a key component to facilitate reward (11) and relieves the negative experience of pain (12)(13)(14). In this report we show that targeted deletion of the MOR gene (Oprm1) significantly alters the brain connectome in living mice and predominantly reshapes the so-called reward/aversion network involved in pain, depression, and suicide (15). Results and DiscussionFine-Grained Mapping of the Mouse Brain Functional Connectome. In a first step, we established fine-grained mapping of the mouse brain functional connectome (MBFC) in control and Oprm1 −/− living mice. Using data-driven spatial independent component analysis (100-ICASSO) (4) of combined blood oxygenation level-dependent (BOLD) resting-state functional MRI (rsfMRI) datasets (Materials and Methods, Data Analysis), we identified 87 functional components, the patterns of which covered neur...

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

“…We further probed the status of whole-brain network activities in live animals, as previously done in (25). Resting-state functional Magnetic Resonance Imaging (Rs-fMRI) and the analysis of whole-brain connectivity (24) showed that the recruitment of DS, NAc and VTA as functional hubs differed in the brain of Dlx-MOR compared to Ctl mice (Figure 2C).…”

“…Animal preparation, data acquisition and analysis were performed as described previously (24, 25), and directionality analysis conducted as described in Supplemental Information.…”

μ opioid receptor, social behaviour and autism spectrum disorder: reward matters

“…The μ receptor null mice thus reproduce the broadest autistic syndrome ever reported in preclinical research, proving unique face validity. Moreover, Oprm1 −/− mice display anatomical, neurochemical and genetic landmarks of the disease, such as modified neuronal activation in anxiety‐ and reward‐associated brain structures, reduced striatal connectivity, altered synaptic morphology and monoamine levels in the striatum and modified expression of several candidate genes of autism, providing construct validity to the model (Becker et al , ; Mechling et al , ). Finally, as regards predictive validity, risperidone and oxytocin, compounds that demonstrated efficiency in relieving autistic features in patients, also alleviated such symptoms in μ receptor null mice (Becker et al , ; Gigliucci et al , ).…”

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

“…Since its onset in 2011 (Jonckers et al, 2011), mouse rsfMRI has developed in a number of centres and has grown to become a routine method with a number of applications, reviewed in (Chuang and Nasrallah, 2017;Gozzi and Schwarz, 2016;Hoyer et al, 2014;Jonckers et al, 2015Jonckers et al, , 2013Pan et al, 2015). Prominently, mouse rsfMRI has been used to investigate an extensive list of models, including Alzheimer's disease (Grandjean et al, 2014b, Shah et al, 2013, 2016cWiesmann et al, 2016;Zerbi et al, 2014), motor (DeSimone et al, 2016;Li et al, 2017), affective (Grandjean et al, 2016a), autism spectrum Haberl et al, 2015;Liska et al, 2018;Liska and Gozzi, 2016;Michetti et al, 2017;Sforazzini et al, 2016;Zerbi et al, 2018;Zhan et al, 2014), schizophrenia (Errico et al, 2015;Gass et al, 2016), pain (Buehlmann et al, 2018;Komaki et al, 2016), reward (Charbogne et al, 2017;Mechling et al, 2016), and demyelinating disorders (Hübner et al, 2017). Another application of mouse rsfMRI is the elucidation of large-scale functional alterations exerted by pharmacological agents (Razoux et al, 2013;Shah et al, 2016aShah et al, , 2015.…”