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.
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|Ben Hamida, Sami; Mendonça-Netto, Sueli; Arefin, Tanzil Mahmud et al. (2018) Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks. Biol Psychiatry 84:202-212|
|Maroteaux, G; Arefin, T M; Harsan, L-A et al. (2018) Lack of anticipatory behavior in Gpr88 knockout mice showed by automatized home cage phenotyping. Genes Brain Behav 17:e12473|
|Ehrlich, Aliza T; Semache, Meriem; Bailly, Julie et al. (2018) Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing. Brain Struct Funct 223:1275-1296|
|Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie (2017) Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. Addict Biol 22:1205-1217|
|Meirsman, A C; de Kerchove d'Exaerde, A; Kieffer, B L et al. (2017) GPR88 in A2A receptor-expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating. Eur J Neurosci 46:2026-2034|
|Boulos, Laura-Joy; Darcq, Emmanuel; Kieffer, Brigitte Lina (2017) Translating the Habenula-From Rodents to Humans. Biol Psychiatry 81:296-305|
|Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena et al. (2017) Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. Biol Psychiatry 81:778-788|
|Meirsman, Aura C; Le Merrer, Julie; Pellissier, Lucie P et al. (2016) Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist. Biol Psychiatry 79:917-27|
|Chu Sin Chung, Paul; Keyworth, Helen L; Martin-Garcia, Elena et al. (2015) A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons. Biol Psychiatry 77:404-15|
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