Tracking and regulation of nicotine dependence in the insular cortex

项目摘要 这项提议的中心目标是描述岛叶皮质(InsCtx)在编码中的作用 并塑造尼古丁依赖小鼠摄入尼古丁的生理动力。InsCtx 整合了感觉、内脏和边缘信息，并与内感有关：内感 身体状态。内感在成瘾的发展中起着至关重要的作用，因为奖赏效应 令人上瘾的药物和戒断的令人厌恶的方面在很大程度上是身体上的感觉。 人类吸烟者的功能成像显示，InsCtx对与吸烟相关的线索的反应随着自我增加而增加 报告的渴望强度和获得尼古丁的预期。耐人寻味的是，在涉及 在InsCtx，吸烟者报告戒烟率增加，尼古丁渴望减少。尽管如此，它还是 目前尚不清楚InsCtx是如何编码尼古丁充足和戒断状态的 尼古丁依赖，以及是否有针对性的InsCtx操作可以抑制暗示的尼古丁寻求行为。这一差距 在理解方面，部分原因是我们无法跟踪整个大脑中大量神经元的活动 对尼古丁(或其他成瘾药物)的依赖和戒断。我已经克服了这一点 通过采用我们实验室的慢性双光子钙成像的概念和技术框架来应对挑战 饥饿/口渴转换期间数百个InsCtx神经元以研究InsCtx对尼古丁状态和 尼古丁预测线索。具体地说，我建议在小鼠(I)产生尼古丁的过程中跟踪InsCtx神经元 通过家庭笼子饮用水暴露的依赖，以及(2)学习对视觉提示的反应，以便接收 口服尼古丁奖励。在目标1中，我将检验这样一个假设，即当动物对尼古丁产生依赖时， InsCtx正在进行的编码饱腹感状态的活动模式将随着时间的推移而改变，以反映这一新的身体 州政府。由于尼古丁对大脑的中枢以及对身体生理的外围都有直接影响，我 将使用自然和药物操作来确定正在进行的InsCtx活动模式是否反映了 尼古丁的中枢和/或外周作用。在目标2中，我将研究InsCtx如何对尼古丁做出反应- 预测线索与核内中脑边缘多巴胺释放的同步记录相关 伏隔物质，众所周知，它调节成瘾药物的一些有益方面，并深刻地 在上瘾的状态下改变的。然后我将测试InsCtx的急性光遗传沉默将 干扰对尼古丁预测线索的习得的多巴胺能和行为反应。这些实验将 增进我们对InsCtx活性模式在尼古丁出现过程中如何变化的理解 并将定义InsCtx在药物寻找行为中的作用。这项工作将提高我们的 了解尼古丁暴露如何改变与“生理性”相关的神经表征 在药物依赖的发展过程中的饱足感，并可能有助于建立一个新的操作的基础 岛叶皮质活动，实现尼古丁使用障碍患者寻求药物行为的减少。

Project Summary The central goal of this proposal is to characterize the role of the insular cortex (InsCtx) in encoding and shaping the physiological drive to consume nicotine in nicotine-dependent mice. The InsCtx integrates sensory, visceral, and limbic information and is implicated in interoception: the sensing of internal bodily states. Interoception plays a crucial role in the development of addiction because the rewarding effects of addictive drugs and the aversive aspects of withdrawal are largely experienced as bodily sensations. Functional imaging in human smokers shows that InsCtx responses to smoking-related cues increase with self- reported craving intensity and with the expectancy of receiving nicotine. Intriguingly, after strokes involving the InsCtx, smokers report increased rates of smoking cessation and fewer nicotine cravings. Nevertheless, it remains unclear how the InsCtx encodes nicotine-replete and withdrawal states during the development of nicotine dependence, and if targeted InsCtx manipulations can curb cued nicotine-seeking behaviors. This gap in understanding is due in part to our inability to track the activity of large numbers of neurons throughout the development of dependence on and withdrawal from nicotine (or other addictive drugs). I have overcome this challenge by adapting our lab’s conceptual and technical framework for chronic two-photon calcium imaging of hundreds of InsCtx neurons during shifts in hunger/thirst to investigate InsCtx encoding of nicotine states and nicotine-predicting cues. Specifically, I propose to track InsCtx neurons as mice (i) develop nicotine dependence via home-cage drinking water exposure, and (ii) learn to respond to visual cues in order to receive oral nicotine rewards. In Aim 1, I will test the hypothesis that as an animal becomes dependent on nicotine, the pattern of InsCtx ongoing activity encoding states of satiety will change across days to reflect this new bodily state. Because nicotine has direct effects centrally on the brain as well as peripherally on bodily physiology, I will use natural and pharmacological manipulations to determine if ongoing InsCtx activity patterns reflect the central and/or peripheral actions of nicotine. In Aim 2, I will examine how InsCtx responses to nicotine- predicting cues correlate with concurrent recordings of mesolimbic dopamine release in the nucleus accumbens, which is known to mediate some of the rewarding aspects of addictive drugs and is profoundly altered in states of addiction. I will then test the hypothesis that acute optogenetic silencing of the InsCtx will disrupt learned dopaminergic and behavioral responses to nicotine-predicting cues. These experiments will advance our understanding of how InsCtx activity patterns change during the emergence of nicotine dependence, and will define the role of the InsCtx in drug-seeking behaviors. This work will improve our understanding of how exposure to nicotine modifies the neural representations associated with ‘physiological satiety’ during the development of drug dependence, and may help establish a basis for novel manipulations of insular cortex activity that achieve reductions in drug-seeking behaviors in patients with nicotine use disorders.