Tracking and regulation of nicotine dependence in the insular cortex

项目摘要 该提案的中心目标是描述岛叶皮层（InsCtx）在编码中的作用。 并在尼古丁依赖小鼠中塑造消耗尼古丁的生理驱动力。InsCtx 整合了感觉、内脏和边缘系统的信息，并与内感受有关： 身体状态内感受在成瘾的发展中起着至关重要的作用，因为奖励效应 成瘾药物的成瘾性和戒断的令人厌恶的方面在很大程度上是作为身体感觉来体验的。 人类吸烟者的功能成像显示，InsCtx对吸烟相关线索的反应随着自我意识的增强而增加。 报告渴望强度和接受尼古丁的预期。有趣的是，在中风后， 吸烟者报告戒烟率增加，尼古丁渴望减少。但它 目前尚不清楚InsCtx如何编码尼古丁充满和戒断状态的发展过程中， 尼古丁依赖，如果有针对性的InsCtx操作可以抑制线索尼古丁寻求行为。这一差距 在理解中的部分原因是我们无法跟踪整个大脑中大量神经元的活动。 发展对尼古丁（或其他成瘾药物）的依赖和戒断。我已经克服了这个 通过调整我们实验室的慢性双光子钙成像的概念和技术框架， 在饥饿/口渴的转变期间，数百个InsCtx神经元研究尼古丁状态的InsCtx编码， 尼古丁预测线索具体来说，我建议跟踪InsCtx神经元作为小鼠（i）开发尼古丁 依赖通过家庭笼饮用水暴露，和（ii）学会响应视觉线索，以接收 口服尼古丁奖励。在目标1中，我将检验一个假设，即当动物对尼古丁产生依赖时， 编码饱腹感状态的InsCtx持续活动模式将在几天内发生变化，以反映这种新的身体状况。 状态由于尼古丁对大脑中枢和身体生理学外周都有直接影响， 将使用自然和药理学操作来确定持续的InsCtx活性模式是否反映了 尼古丁的中枢和/或外周作用。在目标2中，我将研究InsCtx对尼古丁的反应- 预测线索与中脑边缘核多巴胺释放的同步记录相关 众所周知，它可以调解成瘾药物的一些奖励方面， 在成瘾状态下改变。然后，我将测试InsCtx的急性光遗传学沉默将导致 干扰学习多巴胺和行为反应尼古丁预测线索。这些实验将 推进我们对InsCtx活性模式在尼古丁出现期间如何变化的理解 依赖性，并将定义InsCtx在药物寻求行为中的作用。这项工作将提高我们的 了解暴露于尼古丁如何改变与“生理”相关的神经表征 饱腹感“在药物依赖的发展过程中，并可能有助于建立一个新的操纵的基础， 岛叶皮层活动，减少尼古丁使用障碍患者的药物寻求行为。

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.