Neuroimmunomodulation of nicotine relapse and synaptic plasticity

项目总结/摘要 烟草滥用是一个重大的健康问题，仍然是美国可预防死亡的主要原因。 美国成年人中有近五分之一的人死亡。戒烟治疗策略，如 尼古丁替代疗法或伐尼克兰（Chantix®）在帮助个体 戒烟然而，即使对于接受替代疗法的个体，高复发率也持续存在， 强调需要更全面地了解尼古丁成瘾的神经生物学基础 和复吸，以更好地促进长期戒烟。适应不良的神经元可塑性 在几种主要的滥用药物中都有牵连，这些突触改变介导了相关的 在环境刺激和滥用药物之间发生的学习过程。特别是线索诱导 大鼠尼古丁寻求的恢复与介质的快速、瞬时突触增强（t-SP）有关。 树突棘的增加测量了丘脑核核心（NAcore）中的棘神经元（MSN） 头部直径（dh）以及细胞外基质金属蛋白酶（MMPs）的活化。底层 调节这种结构和功能可塑性的分子和细胞机制仍然很差 明白特别是，尚不清楚神经炎症机制是否调节这些蛋白的表达。 突触改变因此，我建议检查促炎性肿瘤坏死因子α（TNFα）的作用， 和NF-κB信号对NAcore中t-SP的影响。 具体来说，我假设病毒载体介导的IκB激酶（IKK，激活NF-κB）抑制 信号转导将减弱NAcore和线索诱导的尼古丁恢复中的t-SP，而IKK的激活 将加强这些措施。此外，我认为TNFα信号转导是突触后t-SP、MMP 激活和线索诱导的尼古丁寻求恢复。这项研究有可能发现一种新的 突触后t-SP响应药物相关刺激而产生的机制。同样， 研究可能揭示了神经炎症机制在药物复发中的新的动态作用， 指导新型有效药物治疗药物的未来开发。的整个持续时间 建议研究，我将在共聚焦显微镜训练，三维分析树突棘 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.