Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice
G protein-coupled receptors are key signaling molecules and major targets for pharmaceuticals. The concept of ligand-dependent biased signaling raises the possibility of developing drugs with improved efficacy and safety profiles, yet translating this concept to native tissues remains a major challenge. Whether drug activity profiling in recombinant cell-based assays, traditionally used for drug discovery, has any relevance to physiology is unknown. Here we focused on the mu opioid receptor, the unrivalled target for pain treatment and also the key driver for the current opioid crisis. We selected a set of clinical and novel mu agonists, and profiled their activities in transfected cell assays using advanced biosensors and in native neurons from knock-in mice expressing traceable receptors endogenously. Our data identify Gi-biased agonists, including buprenorphine, and further show highly correlated drug activities in the two otherwise very distinct experimental systems, supporting in vivo translatability of biased signaling for mu opioid drugs.
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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.