Neural Pathways Underlying Learning with Nicotine Stimulus

烟草使用是全球可预防死亡的主要原因。这种习惯不仅使人衰弱， 个人吸烟者，也包括他们周围的人（二手烟）。尼古丁是主要的成瘾物质 烟草是烟草的一种成分，人们一直在努力了解它的主要强化作用， 主要的刺激效应，包括奖励，镇痛，以及许多其他的心理激活。 尽管尼古丁是一种非常温和的兴奋剂，但仍有更多的人使用烟草，无法戒烟。 然后是所有那些滥用非法物质的人。这表明，除了尼古丁的强化， 其他一些过程可能会导致尼古丁依赖。研究人员和从业人员 越来越意识到某些形式的联想学习与了解吸毒特别相关， 和虐待吸烟者在大量存在的奖励刺激物如食物的存在下经历尼古丁状态， 酒精、工作刹车或同伴互动等等。研究学习的神经基质 尼古丁刺激与其他奖励相关的机制是非常重要的，如果目标是 使用汇聚证据方法制定更有效的治疗策略。开始填充这个 我们对尼古丁刺激下的联想学习所涉及的神经基质的理解存在重大差距， 我们将对初步研究进行随访，这些研究表明，前后背内侧尾壳核 在尼古丁学习的早期和晚期阶段有差异。因为尾壳核是 基底神经节的组成部分，具有来自皮质区的广泛输入和对 苍白球和黑质，我们假设，传入和传出通路连接到 背内侧尾壳核对于尼古丁刺激的联想学习至关重要。因此，研究 本申请中提出的建议将通过更仔细地检查 前、后背内侧尾壳核及其传出和传入的功能受累 尼古丁刺激下的联想学习。为了做到这一点，我们将使用相关 静脉输注模型和尼古丁自我给药模型，其中尼古丁输注与 液体蔗糖的入口这些模型产生尼古丁-蔗糖关联的稳健学习，揭示为 静脉内尼古丁输注后勺形入口增加。以高水平的靶向感兴趣的途径 我们将使用双病毒方法，包括输注表达CRE重组酶的犬 腺病毒-2进入具有神经末梢的区域，并输注CRE依赖的腺相关病毒 进入细胞体所在的区域。我们假设抑制传入和传出通路 连接到背内侧尾壳核将抑制关联学习的获得和表达， 尼古丁刺激从这些实验中获得的知识将填补我们理解的一个重要空白。 神经通路可能导致烟草依赖的顽固性。

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the primary addictive component of tobacco and there have been a significant effort to understand its primary reinforcing and primary stimulus effects that include reward, analgesia, and psychomotor activation among many others. Despite the fact that nicotine is a very mild reinforcer, there are more people using and unable to quit tobacco products then all of those abusing illicit substances. This indicates that in addition to nicotine's reinforcing effects some other processes likely contribute to nicotine dependence. Researchers and practitioners are increasingly aware that some forms of associative learning are particularly relevant to understanding drug use and abuse. Smokers experience nicotine state in a presence of abundantly present rewarding stimuli like food, alcohol, work brakes, or peer interaction to name a few. Investigating neural substrates underlying learning mechanisms with nicotine stimulus associated with other rewards is of great importance if the goal is to develop more efficacious treatment strategies using a converging evidence approach. To start filling this significant gap in our understanding of neural substrates involved in associative learning with nicotine stimulus, we will follow-up on the preliminary studies showing that anterior and posterior dorsomedial caudate-putamen are differentially involved in early and late stages of learning with nicotine. Because caudate-putamen is an integral part of the basal ganglia, with extensive input from cortical areas and prominent inhibitory output to pallidum and substantia nigra, we hypothesize that the afferent and efferent pathways connecting to dorsomedial caudate-putamen are critical for associative learning with nicotine stimulus. Thus the research proposed in this application will programmatically build on our previous findings by examining more closely the functional involvement of anterior and posterior dorsomedial caudate-putamen and their efferent and afferent connections in associative learning with nicotine stimulus. To do so we will use translationally relevant intravenous infusion model and nicotine self-administration model where nicotine infusions are paired with access to liquid sucrose. These models produce robust learning of nicotine-sucrose association revealed as elevated dipper entries following intravenous nicotine infusion. To target pathways of interest with high level of precision we will use double viral approach which includes an infusion of CRE-recombinase expressing canine adenovirus-2 into the areas with neural terminals and an infusion of CRE-dependent adeno-associated virus into the area where cell bodies are located. We hypothesize that inhibiting afferent and efferent pathways connecting to dorsomedial caudate-putamen will inhibit acquisition and expression of associative learning with nicotine stimulus. Knowledge gained from these experiments will fill an important gap in our understanding of neural pathways potentially contributing to the tenacity of tobacco dependence.