Tracking and regulation of nicotine dependence in the insular cortex

岛叶皮质尼古丁依赖性的跟踪和调节

基本信息

批准号：
10604925
负责人：
Kathryn Elizabeth Evans
金额：
$ 4万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604925
关键词：
Acute Affect Animals Area Behavior Behavioral Brain Brain region Calcium Chronic Cigarette Clinical Consumption Cues Decision Making Dependence Development Dopamine Drug Addiction Esthesia Expectancy Food Functional Imaging Future Goals Head Home Human Hunger Image Individual Intake Interoception Learning Measurement Mediating Mus Nature Neurons Nicotine Nicotine Dependence Nicotine Use Disorder Nicotine Withdrawal Nicotinic Receptors Nucleus Accumbens Oral Patient Self-Report Patients Pattern Perception Peripheral Pharmaceutical Preparations Photometry Physiological Physiology Play Population Preparation Protocols documentation Regulation Reporting Rewards Role Satiation Sensory Shapes Signal Transduction Smell Perception Smoker Smoking Stroke Taste Perception Testing Thirst Time Training Visceral Visual Water Withdrawal Work addiction antagonist behavioral response bodily sensation cell cortex craving drinking water drug development drug seeking behavior experience experimental study hedonic imaging study improved insight mouse model neural nicotine craving nicotine cue nicotine exposure nicotine reward nicotine seeking behavior nicotine treatment nicotine use novel optogenetics pharmacologic post stroke response sensory integration smoking cessation tobacco smokers two-photon

项目摘要

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.

项目概要该提案的中心目标是描述岛叶皮层 (InsCtx) 在编码中的作用并塑造尼古丁依赖小鼠消耗尼古丁的生理动力。整合感觉、内脏和边缘信息，并参与内感受：内部感觉身体状态在成瘾的发展中起着至关重要的作用，因为奖励效应。成瘾药物的影响和戒断带来的厌恶情绪在很大程度上都是通过身体感觉来体验的。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调节的增加而增加。有趣的是，在涉及中风后，他们对尼古丁的渴望强度和期望程度。在 InsCtx 中，吸烟者报告戒烟率增加，对尼古丁的渴望减少。目前尚不清楚 InsCtx 在发育过程中如何编码尼古丁充足和戒断状态尼古丁依赖，如果有针对性的 InsCtx 操作可以抑制暗示的尼古丁寻求行为，那么这一差距。理解上的困难部分是由于我们无法跟踪整个过程中大量神经元的活动我已经克服了对尼古丁（或其他成瘾药物）的依赖和戒断。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来应对挑战数百个 InsCtx 神经元在饥饿/口渴转变期间研究 InsCtx 编码尼古丁状态和具体来说，我建议在小鼠 (i) 产生尼古丁时追踪 InsCtx 神经元。通过接触家笼饮用水来消除依赖性，以及（ii）学会对视觉提示做出反应，以便接受在目标 1 中，我将测试以下假设：当动物变得依赖尼古丁时，编码饱腹感状态的 InsCtx 持续活动模式将在几天内发生变化，以反映这个新的身体因为尼古丁对大脑的中枢和身体的生理机能都有直接影响，我将使用自然和药理学操作来确定持续的 InsCtx 活动模式是否反映了在目标 2 中，我将研究 InsCtx 对尼古丁的反应。预测与核内中脑边缘多巴胺释放的同时记录相关的线索众所周知，伏隔核可以调节成瘾药物的一些有益方面，并且具有深远的影响然后我将测试 InsCtx 的急性光遗传学沉默会改变的假设。这些实验将扰乱对尼古丁预测线索的多巴胺能和行为反应。增进我们对 InsCtx 活动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。这项工作将改善我们的研究。了解接触尼古丁如何改变与“生理学”相关的神经表征药物依赖发展过程中的“饱腹感”，可能有助于为新的操纵方法奠定基础岛叶皮质活动可减少尼古丁使用障碍患者的药物寻求行为。