Administrative Supplement: Dynamic Signaling of NRG3-ErbB4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes

We have previously shown that multiple single-nucleotide polymorphisms (SNPs) across the Neuregulin 3 (NRG3) gene significantly associate with smoking cessation outcomes in two independent cohorts of smokers.7 We now have new evidence that SNPs previously identified to increase NRG3 expression are significantly associated with nicotine withdrawal phenotypes in smokers. Our published murine experimentsdemonstrate that this increased NRG3 expression may be responsible for affective nicotine withdrawal (WD) phenotypes in particular: (1) chronic nicotine and 24hWD increase mRNA and protein expression of NRG3 and its receptor, ErbB4, in the ventral hippocampus, (2) genetic interruption of NRG3 signaling blocks expression of nicotine WD anxiety-like phenotypes in the Novelty-induced Hypophagia Test, a model shown to be dependent upon ventral hippocampal function, and (3) inhibition of ErbB4, the NRG3 receptor, by Afatinib reduced anxiety-like behaviors during WD in this same behavioral model. While this is persuasive evidence for the role of ventral hippocampal NRG3 signaling in modulating affective nicotine WD phenotypes, little is known regarding the precise mechanisms through which NRG3 and nicotine interact. Therefore, the current overall goal of this funded R01 funded proposal is to systematically investigate the cell-specific role of the NRG3-ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To achieve this, the aims of this funded parent grant are: (1) Is NRG3-ErbB4 signaling between pyramidal cells and interneurons in the hippocampus necessary for expression of nicotine WD-induced anxiety? (2) Does the location of nicotinic receptors and NRG3/ErB4 dictate chronic nicotine and 24hWD effects on cellular cascades and glutamatergic input? (3) How does nicotine-mediated NRG3-ErbB4 signaling regulate the activity of CCK+ and PV+ cells to influence the dynamic properties of the hippocampal circuit? This diversity supplement proposal primarily focused on the impact of Nrg3-ErbB4 and canonical PI3K - mTOR downstream signaling in PV+ cells within the VH on chronic nicotine administration and WD. Since a great body of literature suggests a functional interaction of nicotine and opioid systems in drug-seeking and mu-opioid and ErbB4 receptors are co-expressed in PV interneurons, this supplement also aims to investigate whether NRG3-ErbB4 signaling underlies the development and maintenance of opioid dependence.