6875 Boulevard Lasalle
Scientific Director at the Douglas Mental Health University Institute
Professor, Department of Psychiatry, McGill University
Chair, Monique H. Bourgeois in Pervasive Developmental Disorders, Faculty of Medicine of McGill University
Canada Research Chair in Neurobiology of Addiction and Mood Disorders
G protein-coupled receptors in brain function and disease
The Kieffer laboratory, newly established at the Douglas Research Center/McGill is interested in G protein coupled receptors in mental health and disease. G protein coupled receptors (GPCRs) are major targets in biomedicine and show huge potential for psychiatric disorders. Our goal is to elucidate where and how GPCRs control neuronal signaling and functional connectivity in the living brain to regulate normal and pathological behavior. Towards this goal, we develop and study customized mice with targeted GPCR gene mutations (conditional knockout, knock-in). We develop pioneering approaches towards (i) unbiased behavioral phenotyping to challenge both neural processes and symptomatology, (ii) hyperresolutive non-invasive brain imaging in living animals that combines structural and functional Magnetic Resonance Imaging and (iii) cutting-edge molecular imaging of GPCR signaling in vivo using multiphoton microscopy to connect neuronal signaling with network activities. Emphasis is (i) on opioid receptors, to study reward processing and implication in addiction, depression and autism syndrome disorders, and (ii) selected orphan GPCRs (oGPCRs), whose functions in the brain remain unknown, for discovery programs.
1. Kieffer, B.L., Befort, K., Gaveriaux-Ruff, C. and Hirth, C.G. (1992) The delta-opioid receptor : expression cloning and pharmacological characterisation. Proc. Natl. Acad. Sci. USA 89, 12048-12052 PMID: 1334555
2. Matthes, H. W. D., Maldonado, R., Simonin, F., Valverde, O., Slowe, S., Kitchen, I, Befort, K., Dierich, A., Le Meur, M., Dollé, P., Tzavara, E., Hanoune, J., Roques, B. P. and Kieffer, B. L. (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid receptor gene Nature 383, 819-823 PMID: 8893006
3. Filliol D., Ghozland S., Chluba J., Martin M., Matthes H. W., Simonin F., Befort K., Gavériaux-Ruff C., Dierich A., LeMeur M., Valverde O., Maldonado R. and Kieffer B. L. (2000) Mu- and delta-opioid receptor-deficient mice exhibit opposing alterations of emotional responses. Nature Genetics 25, 195-199 PMID: 10835636
4. Kieffer B. L. and Evans C. J. Opioid tolerance – In search of the holy grail. (2002) Cell 108, 1-20.
5. Décaillot, F., Befort K., Filliol, D., Yue, S-Y., Walker, P. and Kieffer B. L. (2003) Opioid receptor random mutagenesis: how a G protein coupled receptor turns on. Nature Structural Biology 10, 629-636. PMID: 12847517
6. Moles A., Kieffer B. L. and D’Amato F. R. (2004) Deficit in attachment behaviour in mice lacking the µ-opioid-receptor gene Science 304,1983-6. PMID: 15218152
7. Scherrer G., Tryoen-Tóth P., Filliol D., Matifas A., Laustriat D., Cao Y. Q., Basbaum A. I., Dierich D., Vonesh J.-L., Gavériaux-Ruff C. and Kieffer B. L. (2006) Knock-in mice expressing fluorescent delta opioid receptors uncover G protein coupled receptor dynamics in vivo Proc. Natl. Acad. Sci. USA 103, 9691-6. PMID: 1676665
8. Olmstead C., Ouaggazzal A-M. and Kieffer B. L. (2009) Mu and delta opioid receptors oppositely regulate motor impulsivity in the signaled nose poke task PLoS ONE 4 : 2, e4410. Cited in the Editor’s choice section of Science (2009) 323, 984-985. PMID: 19198656
9. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O’Donnell D, Kieffer BL and Basbaum AI. (2009) Dissociation of the opioid receptor mechanisms that control mechanical and thermal pain. Cell 137, 1148-59. PMID: 19524516
10. Goeldner C, Lutz PE, Darcq E, Halter T, Clesse D, Ouagazzal AM, Kieffer BL (2010) Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. Biol. Psy. PMID: 20947067. Selected for a Press Release by Editor in Chief.
11. Nozaki C, Vergnano AM, Filliol D, Ouagazzal A-M, Le Goff A, Carvalho S, Matifas A, Gaveriaux-Ruff C, Neyton J, Paoletti P and Kieffer BL (2011). Zinc alleviates pain through High-affinity binding to the NMDA receptor NR2A subunit Nature Neurosci 14, 1017. PMID: 21725314.
12. Lutz PE and Kieffer BL (2013) The multiple facets of opioid receptor function: implications for addiction. Curr Opin Neurobiol. 23(4):473-9. PMID: 23453713.
13. Becker JA, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, Kieffer BL (2014) Autistic-Like Syndrome in mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity. Neuropsychopharmacology. 39(9):2049-60 PMID: 24619243
14. Y Cui, SB Ostlund, A James, CS Park, KW Roberts, N Mittal, N Murphy, BL Kieffer, D Jentsch, W Walwyn, CJ Evans, NT Maidment and XW Yang. (2014) Mu-Opioid Receptors in a Subpopulation of Striatal Direct-Pathway Neurons Can Mediate Opiate Reinforcement. Nature Neuroscience 17(2):254-61 PMID: 24413699
15. Chu Sin Chung P, Keyworth HL, Martin-Garcia E, Bailey A, Befort K, Filliol D, Matifas A, Charbogne P, Darcq E, Ouagazzal A-M, Gavériaux-Ruff C, Maldonado R, Kitchen I and Kieffer BL. (2015) A novel anxiogenic role for the delta opioid receptor expressed in forebrain GABAergic neurons Biological Psychiatry 77(4):404-15 PMID: 25444168
B. L. Kieffer is Professor at the Dpt Psychiatry, McGill University and the Scientific Director of the Douglas Mental Health Research Center in Montréal since 2014. She also is Professor at the Université de Strasbourg France, where she developed most her past research activity (IGBMC, one of the leading European centres of biomedical research). She has isolated the first gene encoding an opioid receptor, opening an entire research field towards understanding the molecular basis of opioid-controlled behaviors. Her genetic dissection of the opioid system has brought major advances in pain, addiction and mood disorders research, as well as in the area of molecular pharmacology and G protein coupled receptor research. She has developed and shared exquisite genetic tools worldwide, and has developed innovative research lines with strong impact in neuroscience and biomedical research. She has received numerous awards, including the Lounsbery (French and US Academies of Science) and the Lamonica Award of Neurology (French Academy of Science). In march 2014, she also received the International L’OREAL-UNESCO Award for Women in Science (European Laureate). She became an EMBO (European Molecular Biology Organization) member in 2009 and was elected as a member of the French Academy of Sciences in 2013.
Prix L'Oréal-UNESCO Pour les Femmes et la Science - Fondation L'Oréal et l'UNESCO - 2014
Member of the French Academy of science - Académie des sciences - 2013
Lamonica prize for neurology - Académie des sciences - 2012
Chevalier of the Legion of Honor - Etat français - 2012
Member of the European Molecular Biology Organization (EMBO) - European Molecular Biology Organization (EMBO) - 2009
Yvon Lamour Prize - Association France Alzheimer - 2007
Richard Lounsbery Prize - Institut de France de l'Académie des Sciences – 2004
Award "Jules Martin" - The French Academy of Sciences - 2001
Junior Member of the "Institut Universitaire de France" - 1994-1999
Brigitte Kieffer, PhD, Principal Investigator
Emmanuel Darcq, PhD, Academic Associate
Sami Benhamida, PhD, Research Associate
Aliza Ehrlich, PhD, Post-Doctoral Fellow
Grégoire Maroteaux, PhD, Post-Doctoral Fellow
Md. Taufiq Nasseef, PhD, Post-doctoral Fellow
Julie Bailly, PhD Student
Laura-Joy Boulos, PhD Student
Florence Gross, MSc, Research Assistant
Aimée-Lee Luco, MSc, Research Assistant
Maria Osikowicz, PhD, Research Coordinator
Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. Biol Psychiatry. 2017;81(9):778-788.
Translating the Habenula-From Rodents to Humans. Biol Psychiatry. 2017;81(4):296-305.
Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function. J Neurosci. 2016;36(12):3541-51.
Impact of chronic morphine on delta opioid receptor-expressing neurons in the mouse hippocampus. Neuroscience. 2016;313:46-56.
Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons. J Neurosci. 2015;35(37):12917-31.
Interaction of CRF and kappa opioid systems on GABAergic neurotransmission in the mouse central amygdala. J Pharmacol Exp Ther. 2015;355(2):206-11.
Knock-In Mice with NOP-eGFP Receptors Identify Receptor Cellular and Regional Localization. J Neurosci. 2015;35(33):11682-93.
Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist. Biol Psychiatry. 2016;79(11):917-27.
In vivo neuronal co-expression of mu and delta opioid receptors uncovers new therapeutic perspectives. Receptors Clin Investig. 2014;1(5).
Dissociation of heroin-induced emotional dysfunction from psychomotor activation and physical dependence among inbred mouse strains. Psychopharmacology (Berl). 2015;232(11):1957-71.
Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. Behav Brain Res. 2015;278:429-34.
A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. Biol Psychiatry. 2015;77(4):404-15.
VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat Neurosci. 2014;17(12):1751-8.
Expression of mu opioid receptor in dorsal diencephalic conduction system: new insights for the medial habenula. Neuroscience. 2014;277:595-609.
In vivo properties of KNT-127, a novel δ opioid receptor agonist: receptor internalization, antihyperalgesia and antidepressant effects in mice. Br J Pharmacol. 2014;171(23):5376-86.
Zinc dynamics and action at excitatory synapses. Neuron. 2014;82(5):1101-14.
A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct Funct. 2015;220(2):677-702.
Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology. 2014;39(9):2049-60.
Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat Neurosci. 2014;17(2):254-61.
15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology. 2014;76 Pt B:204-17.
GPR88 in A2AR Neurons Enhances Anxiety-Like Behaviors. eNeuro. 2016;3(4).
Drug discovery: Designing the ideal opioid. Nature. 2016;537(7619):170-171.