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

项目摘要/摘要 近80%的吸烟者试图戒烟，但都失败了。虽然人们对基因的认识有所增加 对这一统计数据的贡献，其背后的分子机制(S)仍然是我们 知识。我们之前已经证明，多个单核苷酸多态(SNPs)在 神经调节蛋白3(NRG3)基因与两个独立的患者的戒烟结果显著相关 104我们现在有新的证据表明，以前发现的SNPs会增加NRG3 在吸烟者中，表达与尼古丁戒断表型显著相关。我们出版的小鼠 实验104表明，这种NRG3表达的增加可能与情绪性尼古丁有关 戒断(WD)表型：(1)慢性尼古丁和24小时戒断可增加mRNA和蛋白质的表达 NRG3及其受体ErbB4在腹侧海马区的表达；(2)NRG3的基因阻断 在新奇诱导的低吞噬试验中，信号阻断尼古丁WD焦虑样表型的表达 模型显示依赖于腹侧海马功能，以及(3)抑制ErbB4，NRG3 在相同的行为模型中，阿法替尼可减少WD期间的焦虑样行为。虽然这是 海马腹侧NRG3信号在调节情感性尼古丁WD中的作用的有说服力的证据 在表型方面，人们对NRG3和尼古丁相互作用的确切机制知之甚少。 因此，这项提案的总体目标是系统地研究NRG3- 尼古丁治疗和戒断过程中腹侧海马区的ERBB4信号。为了实现这一目标，我们 提出了三个中心问题：1)NRG3-ErbB4信号在锥体细胞和中间神经元之间是否存在 表达尼古丁WD诱导的焦虑所必需的海马体，2)尼古丁的位置 受体和NRG3/ErB4决定慢性尼古丁和24hWD对细胞级联反应和谷氨酸能的影响 (3)尼古丁介导的NRG3-ErbB4信号如何调节CCK+和PV+的活性 细胞影响海马神经元的动态特性？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，产生一个 翻译，高影响假说，检测这一信号通路在 尼古丁和戒断过程中海马体的特定细胞类型。完成这些研究后， 扩大对遗传、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。

PROJECT SUMMARY/ABSTRACT 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.