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

海马 NRG3-ErbB4 的动态信号介导尼古丁戒断表型

• 批准号: 10092135
• 负责人: Jill R. Turner
• 金额: $ 33.36万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092135
• 关键词: Accounting; Affective; Animals; Anxiety; Awareness; Behavior; Behavioral Model; Calcium; Cells; Cholecystokinin; Chronic; Complex; Data; Development; Drosophila acetylcholine receptor alpha-subunit; Electrophysiology (science); ErbB4 gene; Fluorescent in Situ Hybridization; Genes; Genetic; Glutamates; Goals; Hippocampus (Brain); Human; Image; Interneurons; Interruption; Knock-in Mouse; Knowledge; Ligands; Location; Mediating; Modeling; Molecular; Mus; NRG3 gene; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Outcome; Phenotype; Property; Publishing; Pyramidal Cells; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Smoker; Smoking; Surgeon; Testing; Therapeutic; Time; Tissues; Tobacco smoking behavior; United States; Western Blotting; Withdrawal; Withdrawal Symptom; anxiety-like behavior; base; behavior test; cell type; cohort; confocal imaging; density; genetic information; mRNA Expression; nicotine treatment; novel; preventable death; protein expression; receptor; receptor coupling; smoking cessation; tool; voltage sensitive dye; withdrawal-induced anxiety

Nearly 80% of smokers attempting to quit, fail. 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.

近 80% 试图戒烟的吸烟者都失败了。尽管人们越来越重视遗传 尽管对这一统计数据的贡献，其背后的分子机制仍然是我们研究中的一个关键差距 知识。我们之前已经表明，多个单核苷酸多态性（SNP）跨越 神经调节蛋白 3 (NRG3) 基因与两个独立的戒烟结果显着相关 吸烟者群体。104 我们现在有新的证据表明，之前发现的 SNP 可以增加 NRG3 表达与吸烟者的尼古丁戒断表型显着相关。我们发表的小鼠 实验 104 证明 NRG3 表达的增加可能是产生情感尼古丁的原因 戒断 (WD) 表型特别是：(1) 慢性尼古丁和 24hWD 增加 mRNA 和蛋白质 NRG3 及其受体 ErbB4 在腹侧海马的表达，(2) NRG3 的遗传中断 在新奇诱发的吞咽不足测试中，信号传导阻断尼古丁 WD 焦虑样表型的表达，这是一种 模型显示依赖于腹侧海马功能，以及 (3) ErbB4（NRG3）的抑制 阿法替尼受体，在相同的行为模型中减少了 WD 期间的焦虑样行为。” 腹侧海马 NRG3 信号在调节情感尼古丁 WD 中的作用的有说服力的证据 尽管 NRG3 和尼古丁相互作用的确切机制尚不清楚。 因此，该提案的总体目标是系统地研究NRG3-的细胞特异性作用。 尼古丁治疗和戒断期间腹侧海马中的 ErbB4 信号传导。为了实现这一目标，我们 提出了三个核心问题：1) NRG3-ErbB4 信号在锥体细胞和中间神经元之间是否存在？ 海马体对于表达尼古丁 WD 引起的焦虑是必需的吗？, 2) 尼古丁的位置是否 受体和 NRG3/ErB4 决定慢性尼古丁和 24hWD 对细胞级联和谷氨酸能的影响 (3) 尼古丁介导的 NRG3-ErbB4 信号如何调节 CCK+ 和 PV+ 的活性 细胞影响海马回路的动态特性？我们的方法很重要，因为它 结合来自人类和动物研究的集体遗传信息来生成 翻译性的、高影响力的假设检验了该信号通路在 尼古丁和戒断过程中海马体的特定细胞类型。完成这些研究将 扩大对遗传学、电路功能和行为之间复杂相互作用的理解，以便 开发更好、更具体的戒烟辅助工具。