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Description
While there is increased appreciation for genetic
contributions to this statistic, the molecular mechanism(s) underlying this remain a critical gap in our
knowledge. 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.104 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
experiments104 demonstrate 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 it’s 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 overall goal of this proposal is to systematically investigate the cell-specific role of the NRG3-
ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To accomplish this, we
are posing three central questions: 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?, and (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? Our approach is significant because it
combines collective genetic information from both human and animal studies to generate a
translational, high-impact hypothesis examining the functional role of this signaling pathway within the
specific cell-types of the hippocampus during nicotine and withdrawal. Completion of these studies will
expand understanding of the complex interplay between genetics, circuit function, and behavior in order to
develop better, more specific smoking cessation aids.
Status | Finished |
---|---|
Effective start/end date | 4/1/18 → 1/31/24 |
Funding
- National Institute on Drug Abuse: $1,543,056.00
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Projects
- 1 Finished
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Administrative Supplement: Dynamic Signaling of NRG3-ErbB4 in the Hippocampus Mediates Nicotine Withdrawal Phenotypes
Turner, J. (PI)
National Institute on Drug Abuse
4/1/18 → 1/31/23
Project: Research project