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: 10549006
• 负责人: Jill R. Turner
• 金额: $ 11.16万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549006
• 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%的吸烟者试图戒烟，失败。虽然人们越来越重视遗传学， 虽然对这一统计数据的贡献，但其背后的分子机制仍然是我们研究中的一个关键空白。 知识我们先前已经表明，多个单核苷酸多态性（SNP）在整个 神经调节蛋白3（NRG 3）基因与两个独立研究中的戒烟结果显著相关 104我们现在有新的证据表明，以前确定的SNP增加了NRG 3 表达与吸烟者的尼古丁戒断表型显著相关。我们发表的鼠 实验104表明，这种增加的NRG 3表达可能是尼古丁的情感性作用的原因。 戒断（WD）表型特别是：（1）慢性尼古丁和24小时WD增加mRNA和蛋白 NRG 3及其受体ErbB 4在腹侧海马的表达;（2）NRG 3基因的阻断 信号传导阻断尼古丁WD焦虑样表型在新奇诱导的食欲减退试验中的表达， 模型显示依赖于腹侧海马功能，和（3）抑制ErbB 4，NRG 3 在相同的行为模型中，阿法替尼在WD期间减少了焦虑样行为。“虽然这是 腹侧海马NRG 3信号在调节尼古丁WD情感中作用的有说服力的证据 尽管NRG 3与尼古丁的表型不同，但关于NRG 3与尼古丁相互作用的精确机制知之甚少。 因此，本提案的总体目标是系统地研究NRG 3 - 1的细胞特异性作用。 尼古丁治疗和戒断期间腹侧海马中的ErbB 4信号传导为了做到这一点，我们 提出了三个中心问题：1）NRG 3-ErbB 4信号在锥体细胞和中间神经元之间是否存在？ 海马体是表达尼古丁WD诱导的焦虑所必需的吗？2)尼古丁的位置 受体和NRG 3/ErB 4决定了慢性尼古丁和24小时WD对细胞级联反应的影响， 输入？，尼古丁介导的NRG 3-ErbB 4信号通路如何调节CCK+和PV+的活性 细胞影响海马电路的动态特性？我们的方法很重要，因为它 结合人类和动物研究的集体遗传信息， 翻译，高影响力的假设，检查这一信号通路的功能作用， 尼古丁和戒断期间海马体的特定细胞类型。完成这些研究将 扩展对遗传学、电路功能和行为之间复杂相互作用的理解， 开发更好、更具体的戒烟辅助工具。

项目成果

The Role of Microglia in Sex- and Region-Specific Blood-Brain Barrier Integrity During Nicotine Withdrawal.

• DOI: 10.1016/j.bpsgos.2023.08.019
• 发表时间: 2024-01
• 期刊: Biological psychiatry global open science

Sex- and region-specific consequences of chronic nicotine in the murine hippocampus during fear extinction.

在恐惧消退过程中，小鼠海马体中慢性尼古丁的性别和区域特异性后果。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Keady,JackV;Turner,Jill
• 通讯作者: Turner,Jill

Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.

• DOI: 10.1111/ejn.15780
• 发表时间: 2022-09
• 期刊: The European journal of neuroscience

Role of Neuregulin 3-ErbB4 Signaling in a Murine Model of Co-Morbid Nicotine Dependence and Schizophrenia.

Neuregulin 3-ErbB4 信号在尼古丁依赖和精神分裂症共病小鼠模型中的作用。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Prantzalos,Emily;Turner,Jill
• 通讯作者: Turner,Jill