We hypothesize that Nr4a1 and GprBB regulate alcohol intake and dependence, mainly at the level of the extended amygdala (EA), and represent potential targets to treat alcoholism. We will test this hypothesis using conventional and EA-conditional knockout mice for the two candidate genes, as well as for a known gene considered a valid target in alcohol research (the mu opioid receptor). These unique mutant lines will be studied at behavioral (Aim 1) and imaging (Aim 2) levels to characterize implication of the three genes in excessive alcohol drinking.
In Aim 1 we will examine conventional knockout mice available in our laboratory for (i) alcohol withdrawal after chronic intermittent exposure to alcohol vapors (CIE) and (ii) voluntary drinking along a history of exposure to air / alcohol vapors (CIE/TBC) leading to recreational / excessive drinking (Aim la).
In Aim lb we will produce and characterize EA-conditional mice for all three genes by crossing floxed mice and Wfsl-Cre mice, all of which were generated in the past funding period.
In Aim 1 c we will examine conditional mutant lines as in Aim la. Phenotypes in conventional knockout mice will establish a functional role of targeted genes in alcohol intake, and phenotypes in EA-conditional mutant mice will uncover implication of EA circuitry in those behaviors.
In Aim 2, we will use cutting-edge DT-MRI and fiber tracking, and implement FcMRI in mice (coll. J. Hennig, Freiburg, Germany) to identify structural and connectivity remodeling in mice undergoing a history of excessive drinking. Experimental conditions will be optimized in wild-type mice (Aims 2a and d), then applied to mutant mice with strongest behavioral phenotype (data from Aim 1) under conditions of chronic exposure (Aim 2b) or voluntary drinking in the CIE/TBC paradigm (Aim 2c) in longitudinal experiments.
Aim 2 will expand our knowledge of gene function with a dynamic anatomical dimension and provide a framework for translational studies from rodents to humans. Together, the proposal integrates unique mouse genetic tools and imaging methodology, to functionally study novel genes in alcohol dependence at molecular and system levels. Interactions with INIA partners involve sharing of material (mouse lines, AAV-shRNAs) and knowledge (imaging, mice and viruses).
INIA gene expression studies have identified novel candidate genes for alcohol research. We have selected two genes, regulated by alcohol exposure in several studies. Nr4a1 encodes an orphan nuclear receptor that acts as a transcription factor, and Gpr88 encodes an orphan G protein coupled receptor with unknown function. Both receptors are druggable targets expressed in the adult brain. Study of their role in brain function is only beginning and their potential involvement in alcohol addiction has not been examined.
|Gardon, O; Faget, L; Chu Sin Chung, P et al. (2014) Expression of mu opioid receptor in dorsal diencephalic conduction system: new insights for the medial habenula. Neuroscience 277:595-609|
|Charbogne, Pauline; Kieffer, Brigitte L; Befort, Katia (2014) 15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 76 Pt B:204-17|
|Le Merrer, Julie; Befort, Katia; Gardon, Olivier et al. (2012) Protracted abstinence from distinct drugs of abuse shows regulation of a common gene network. Addict Biol 17:1-12|
|Darcq, Emmanuel; Befort, Katia; Koebel, Pascale et al. (2012) RSK2 signaling in medial habenula contributes to acute morphine analgesia. Neuropsychopharmacology 37:1288-96|
|Le Merrer, Julie; Faget, Lauren; Matifas, Audrey et al. (2012) Cues predicting drug or food reward restore morphine-induced place conditioning in mice lacking delta opioid receptors. Psychopharmacology (Berl) 223:99-106|
|Goeldner, Celia; Lutz, Pierre-Eric; Darcq, Emmanuel et al. (2011) Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine. Biol Psychiatry 69:236-44|
|Darcq, Emmanuel; Koebel, Pascale; Del Boca, Carolina et al. (2011) RSK2 signaling in brain habenula contributes to place aversion learning. Learn Mem 18:574-8|
|Le Merrer, Julie; Plaza-Zabala, Ainhoa; Del Boca, Carolina et al. (2011) Deletion of the ? opioid receptor gene impairs place conditioning but preserves morphine reinforcement. Biol Psychiatry 69:700-3|
|Pradhan, Amynah A; Befort, Katia; Nozaki, Chihiro et al. (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci 32:581-90|
|Le Merrer, Julie; Becker, Jerome A J; Befort, Katia et al. (2009) Reward processing by the opioid system in the brain. Physiol Rev 89:1379-412|
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