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Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Nature Neuroscience volume 17, pages 254–261 (2014)Cite this article

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Abstract

μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.

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Figure 1: Generation and characterization of the Rescue mice with targeted expression of MOR in the subpopulation of striatal direct-pathway MSNs in the striosome and NAc.
Figure 2: Restoration of the rewarding and locomotor effects of morphine by Pdyn BAC–driven expression of MOR in Rescue mice.
Figure 3: Selective MOR expression in striosome and NAc direct-pathway MSNs partially rescues opiate self administration.
Figure 4: Pdyn BAC–driven expression of MOR in an otherwise MOR knockout background did not restore morphine analgesia or naloxone-precipitated withdrawal.
Figure 5: Rgs9-cre–mediated deletion of the Pdyn-MOR transgene in the striatum of Rescue-cre mice abolishes morphine reward effects in the CPP assay.
Figure 6: Selective MOR expression in the axonal terminals of direct-pathway MSNs in the VTA and SNc but not midbrain interneurons can restore morphine-induced striatal dopamine release in Rescue mice.

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Acknowledgements

The research is supported by the University of California, Los Angeles (UCLA) Center for Opioid Receptors and Drugs of Abuse funded by the National Institute on Drug Abuse (NIDA) at the US National Institutes of Health (P50 DA005010). X.W.Y. is also supported in part by the David Weil Fund to the Semel Institute at UCLA and the Neuroscience of Brain Disorders Award from The McKnight Endowment Fund for Neuroscience. The Pdyn-MOR BAC transgenic mice were generated at the UCLA Transgenic Core Facility. Flow cytometry was performed by I. Williams and M. Zhou in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility (funded by US National Institutes of Health awards CA-16042 and AI-28697 and by the JCCC, the UCLA AIDS Institute and the David Geffen School of Medicine at UCLA). W.G. and Y.E.S. are supported by the Transcriptome and Epigenetics Core (P50 DA005010) and by the Intellectual and Developmental Disabilities Research Center (IDDRC center grant NIH-P30HD004612). S.B.O. is supported by the NIDA (R01DA029035). Y.E.S. is also supported by the National Natural Science Foundation of China (NSFC, 90919057). N.M. and N.P.M. are partially supported by the Hatos Foundation.

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Authors and Affiliations

  1. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA

    Yijun Cui, Chang Sin Park & X William Yang

  2. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA

    Yijun Cui, Sean B Ostlund, Chang Sin Park, Weihong Ge, Kristofer W Roberts, Nitish Mittal, Niall P Murphy, James David Jentsch, Wendy M Walwyn, Yi E Sun, Christopher J Evans, Nigel T Maidment & X William Yang

  3. Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA

    Yijun Cui, Sean B Ostlund, Chang Sin Park, Kristofer W Roberts, Nitish Mittal, Niall P Murphy, Carlos Cepeda, Michael S Levine, James David Jentsch, Wendy M Walwyn, Christopher J Evans, Nigel T Maidment & X William Yang

  4. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA

    Yijun Cui, Sean B Ostlund, Chang Sin Park, Weihong Ge, Kristofer W Roberts, Nitish Mittal, Niall P Murphy, Carlos Cepeda, Michael S Levine, Wendy M Walwyn, Yi E Sun, Christopher J Evans, Nigel T Maidment & X William Yang

  5. Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA

    Sean B Ostlund, Kristofer W Roberts, Nitish Mittal, Niall P Murphy, Wendy M Walwyn, Christopher J Evans & Nigel T Maidment

  6. Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA

    Alex S James & James David Jentsch

  7. Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA

    Weihong Ge, Carlos Cepeda, Michael S Levine & Yi E Sun

  8. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA

    Weihong Ge & Yi E Sun

  9. Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université de Strasbourg (UdS), Illkirch, France

    Brigitte L Kieffer

  10. Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China

    Yi E Sun

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Contributions

Y.C. and X.W.Y. designed the study, interpreted the results and wrote the manuscript. Y.C. performed experiments, analyzed the data and made Figures 1, 2, 3, 5 and 6a–g and Supplementary Figures 1, 2, 3, 4, 5, 6, 7, 8. S.B.O. and N.T.M. designed and did experiments for and made Figure 6h,i. A.S.J., J.D.J. and W.M.W. did experiments for and made Figure 4. W.G. and Y.E.S. contributed to Figure 1b. C.S.P. contributed to Figure 1 and Supplementary Figure 3. K.W.R., N.M., N.P.M., N.T.M., B.L.K. and C.J.E. contributed to the experimental design, actual experiments and data analyses for Figures 2, 3 and 5 and Supplementary Figures 6 and 7. C.C. and M.S.L. contributed to revision of the manuscript. X.W.Y. and C.J.E. contributed to Supplementary Figure 9.

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Correspondence to X William Yang.

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Integrated supplementary information

Supplementary Figure 1 Immunohistochemical staining of MOR in Drd1-GFP and Drd2-GFP mice.

(a-c) A representative double immunofluorescence staining shows the expression pattern of MOR (red, b, c) and GFP (green, a,c) in the GENSAT Drd1-GFP mouse brain. Scale bar = 50 μm. (d-f) A representative double immunofluorescence staining shows the expression pattern on of MOR (red, e and f) and GFP (green, d and f) the GENSAT Drd2-GFP mouse brain. Scale bar = 50 μm. (g-i) A representative double immunofluorescence staining shows the co-localization of MOR (red, b, c) and GFP (green, a,c) in the GENSAT Drd1-GFP mouse brain. Scale bar = 20 μm. (j-l) A representative double immunofluorescence staining shows the co-localization of MOR (red, e and f) and GFP (green, d and f) the GENSAT Drd2-GFP mouse brain. Scale bar = 20 μm.

Supplementary Figure 2 A example of FACS sorting of the GFP positive but propidium iodide negative neurons from WT (used as negative control) and Pdyn-GFP mice.

Same gating was used for the Drd2-GFP mice. Green dots within the selected area represents the GFP+/propidium iodide- cells been collected.

Supplementary Figure 3 Immunohistochemical staining of MOR in adult WT, MOR-KO and Rescue mice.

(a) WT; (b) MOR-KO; and (c) Rescue mice. The arrows show the expression of MOR in the cortex and brain stem. Ctx, cerebral cortex; Str, striatum; Tha, thalamus; Mid, midbrain, SN, substantia nigra; BS, brain stem. Scare bar = 1 mm.

Supplementary Figure 4 Western blot analysis of expression of striatal MOR in Rescue mice.

(a) Western blot performed on brain lysates isolated from Rescue, MOR-KO and WT control mice. (b) Quantification of relative MOR expression in the striatum. MOR levels were normalized to those observed in the WT mice (H(2)=32.143, p < 0.001, Non-parametric one-way ANOVA on ranking; n=4, WT; n=3, MOR-KO and n=6, Rescue). Values are mean ± SEM. Asterisks indicate p < 0.05.

Supplementary Figure 5 Pdyn-MOR mice and Rescue mice do not exhibit significant deficits in body weight or locomotor behaviors.

(a) The body weights of the WT, Pdyn-MOR, MOR-KO and Rescue mice are not significantly different (F(3, 44)=1.864, p = 0.1497, ANOVA, n = 12 for genotypes). (b and c) Locomotor activities in the open field test were obtained for adult WT, Pdyn-MOR, MOR-KO and Rescue mice (n=8 per genotype). No significant differences were observed in (b floorplane distance (cm) and (c) floorplane moves among the different genotypes. (F(3, 28) = 0.9993, p = 0.2778 for floorplane distance; F(3, 28) = 0.2574, p = 0.9061 for floorplane moves; One-Way ANOVA, n=8 for all groups)

Supplementary Figure 6 Morphine rewarding effect is rescued by Pdyn-BAC-driven expression of the MOR.

(a) An independent cohort of mice are used to show that the CPP deficit in the MOR-KO mice is restored to the WT level in the Rescue mice. (genotype x F(3, 41)=3.887, p = 0.0156, genotype x treatment interaction, two way ANOVA; n=7, WT+morphine group; n=6 in all other groups). (b) The Rgs9-Cre transgene alone has no significant deficits in CPP (F(4,71)=5,338, p = 0.0008; genotype x treatment interaction, two way ANOVA, n=7-9 per group).The WT, MOR-KO, and Rescue/Cre mice are the same group of littermate mice as those shown in Fig. 5b. Values are mean ± SEM. Triple asterisk indicates p < 0.001.

Supplementary Figure 7 Naloxone-precipitated morphine withdrawal syndrome is not significantly restored by Pdyn-BAC driven expression of MOR in the striatal direct-pathway MSN subpopulations.

(a) tremor; (b) wet dog shakes; (c) teeth chattering; (d) sniffing; (e) ptosis; (f) jumping and (g) diarrhea. Results are expressed as means ± SEM. Triple asterisks indicate p < 0.001 and single asterisk indicates p < 0.05.

Supplementary Figure 8 Immunohistochemistry staining of MOR in Rescue/Cre and Rescue mice.

(a). A low magnification image of Rescue/Cre mice showed the striatal MOR expression is abolished. (b-g) Higher magnificent images to compare MOR expression in Rescue mice (b,d,f) and Rescue/Cre mice (c,e,g) in the cortex (b,c), the brain stem (d,e) and substantia nigra (f,g). The result showed Rgs9-Cre can selectively remove in Rescue/Cre mice the expression of MOR in the striatal-direct pathway MSNs and their axonal terminals in SNc, but did not alter MOR expression in the cortex or brain stem compared to Rescue mice.

Supplementary Figure 9 The role of striatal direct-pathway MSNs in the striosome and NAc in regulating striatal dopamine release in our Rescue mice.

MOR is selectively expressed in a subpopulation of striatal direct-pathway MSNs (black dotted circle) located in the striosome and NAc, which form monosynaptic inputs to the DA neurons in VTA and SNc. Opioids (e.g. morphine) binding to MOR on this direct-pathway MSN subpopulation results in the restoration of striatal dopamine release and opiate-driven reward and reinforcement behaviors in the Rescue mice.

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Cui, Y., Ostlund, S., James, A. et al. Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat Neurosci 17, 254–261 (2014). https://doi.org/10.1038/nn.3622

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