Neuroimmunomodulation of nicotine relapse and synaptic plasticity

项目摘要/摘要 烟草滥用是一个重大的健康问题，仍然是美国可预防的死亡的主要原因 占美国成年人死亡人数的近五分之一。戒烟治疗策略，例如 尼古丁替代疗法或varenicline(Chantix®)在帮助个人方面显示了一些临床效果 戒烟吧。然而，即使对接受替代疗法的人来说，复发率仍然很高，这 强调需要更全面地了解尼古丁成瘾的神经生物学基础 并复发，以更好地促进长期戒烟。适应不良的谷氨酸能可塑性 与几种主要的药物滥用有关，这些突触变化调节了关联性 在环境刺激和滥用药物之间发生的学习过程。具体地说，提示诱导 大鼠尼古丁寻求的恢复与快速、瞬时突触增强(t-SP)有关 伏核核心(NAcore)内的棘神经元(MSN)，通过树突棘的增加来测量 头径(Dh)以及细胞外基质金属蛋白酶(MMPs)的激活。潜在的 调节这种结构和功能可塑性的分子和细胞机制仍然很差。 明白了。特别是，目前尚不清楚神经炎性机制是否调节这些基因的表达。 突触改变。因此，我建议研究促炎性肿瘤坏死因子-α(ntf-α)的作用。 以及NAcore中t-SP上的NF-κB信号转导使用线索诱导尼古丁恢复的啮齿动物模型。 具体地说，我假设病毒载体介导的I-κB激酶抑制(IKK，激活核因子-κB) 在NAcore和CUE诱导的尼古丁恢复中，信号将减弱t-SP，而ikk的激活 将加强这些措施。此外，我认为肿瘤坏死因子α信号是突触后t-SP、MMPs的基础 激活，以及线索诱导的尼古丁寻求的恢复。这项研究有可能确定一部小说 突触后t-SP对药物相关刺激的反应机制。同样，这也是 研究可能揭示神经炎症机制在药物复发中的新的和动态的作用，并可能 引导未来新的有效药物疗法的发展。在整个过程中 拟议的研究，我将在共焦显微镜，树突的三维分析方面进行培训 形态学、免疫组织化学和病毒载体介导的遗传操作。

Project Summary/Abstract Tobacco abuse is a significant health concern and remains the leading cause of preventable death in the United States, accounting for nearly one in five deaths in US adults. Smoking cessation treatment strategies, such as nicotine replacement therapy or varenicline (Chantix®), have shown some clinical efficacy in helping individuals quit smoking. However, high rates of relapse persist even for individuals receiving replacement therapy, which highlights the need for a more holistic understanding of the neurobiological underpinnings of nicotine addiction and relapse to better promote long-term abstinence from tobacco use. Maladaptive glutamatergic plasticity has been implicated across several major drugs of abuse and these synaptic alterations mediate the associative learning processes that occur between environmental stimuli and drugs of abuse. Specifically, cue-induced reinstatement of nicotine seeking in rats is associated with rapid, transient synaptic potentiation (t-SP) of medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore), as measured by an increase in dendritic spine head diameter (dh) as well as activation of extracellular matrix metalloproteinases (MMPs). The underlying molecular and cellular mechanisms that modulate this structural and functional plasticity remains poorly understood. Particularly, it is not known if neuroinflammatory mechanisms modulate the expression of these synaptic alterations. Thus, I propose to examine the role of proinflammatory tumor necrosis factor alpha (TNFα) and NF-κB signaling on t-SP in the NAcore using a rodent model of cue-induced nicotine reinstatement. Specifically, I hypothesize that viral-vector mediated inhibition of IκB kinase (IKK, which activates NF-κB) signaling will attenuate t-SP in the NAcore and cue-induced nicotine reinstatement, whereas activation of IKK will potentiate these measures. Additionally, I propose that TNFα signaling underlies postsynaptic t-SP, MMP activation, and cue-induced reinstatement of nicotine seeking. This research has the potential to identify a novel mechanism through which postsynaptic t-SP is produced in response to drug-associated stimuli. As well, this research may reveal a novel and dynamic role for neuroinflammatory mechanisms in drug relapse and may guide the future development of new and effective pharmacotherapeutics. Throughout the duration of the proposed studies, I will be trained in confocal microscopy, three-dimensional analysis of dendritic spine morphology, immunohistochemistry, and viral-vector mediated genetic manipulation.