Anterior insular cortex to dorsolateral striatum neural circuit regulation of binge drinking and habitual behaviors

项目摘要 超过1400万美国人目前有酒精使用障碍（AUD），尽管几十年的研究， 酒精对大脑的影响减少澳元负担的一个主要障碍是了解如何 神经系统的功能障碍导致酒精成瘾的发展和维持。扩大 我们对AUD的理解，我们必须检查新的大脑区域和神经回路，并直接探测这些 酒精的目标。最近人们感兴趣的一个大脑区域，岛叶皮层（insular cortex）， 成瘾循环的专注/预期阶段。先前的一项人类研究表明， 获得性吸烟损害显示吸烟欲望降低，这是吸烟在吸烟中作用的初步证据。 成瘾周期的关注/预期阶段。然而，有新的证据表明，岛屿有一个 在成瘾循环的其他阶段发挥更大的作用。因此，迫切需要研究岛状电路 扩大我们对与AUD相关的神经适应的理解。最近，我们的实验室发现了一种 前岛叶皮层（AIC）和背外侧纹状体（DLS）之间的联系，并建立了 该电路对酒精特别敏感。虽然我们知道AIC-DLS电路功能显示酒精敏感性， 我们不知道这种敏感性如何改变与酒精相关的行为序列。我的初步数据显示 当AIC输入到DLS（AIC→DLS）被通道视紫红质（ChR）靶向并被光激活时， 在口服酒精消耗期间，小鼠在DID期间减少其酒精摄入量。我也发现 光活化并不诱导实时位置偏好，这表明该电路并不直接调节 价态，但可能会改变编码和表达的习惯性行动，都明确界定的纹状体为基础的 已知会因酒精暴露而改变的行为。总之，这些数据表明， 在成瘾循环中的广泛和多样化的作用，超越了先前的专注/预期阶段 但还需要做更多的工作来表征酒精介导的AIC-DLS回路变化。目标1旨在 确定酒精暴露如何改变AIC→DLS回路，以及调节AIC→DLS回路如何改变 酗酒行为目标2研究AIC→DLS电路对下游介质的影响 多刺投射神经元活动，以调节基于纹状体的行为，例如对酒精和 未处理和酒精暴露的动物。总之，这些数据不仅支持AIC作为一个 AUD神经适应的关键介质超越了专注/预期阶段，但也阐明了 由新的酒精敏感回路控制的行为序列。

PROJECT SUMMARY More than 14 million Americans currently have an alcohol use disorder (AUD) despite decades of research into the effect of alcohol on the brain. One major hurdle to reducing the burden of AUD is understanding how dysfunctions in the nervous system lead to the development and maintenance of alcohol addiction. To expand our understanding of AUD, we must examine novel brain regions and neural circuits and directly probe these targets with alcohol. A brain region of recent interest, the insula (insular cortex), has been heavily implicated in the preoccupation/anticipation stage of the addiction cycle. A prior study in humans indicated that smokers who acquired insula damage show reduced urges to smoke, the initial evidence for the insula’s role in the preoccupation/anticipation stage of the addiction cycle. Yet, there is emerging evidence that the insular has an expanded role in other stages of the addiction cycle. Thus, there is a critical need to investigate insular circuitry to expand our understanding of neuroadaptations associated with AUD. Recently, our laboratory discovered a connection between the anterior insular cortex (AIC) and the dorsolateral striatum (DLS) and established that this circuit is uniquely sensitive to alcohol. While we know AIC-DLS circuit function displays alcohol sensitivity, we do not know how this sensitivity alters alcohol-related behavioral sequences. My preliminary data indicates that when AIC inputs to the DLS (AIC→DLS) are targeted with channelrhodopsin (ChR) and photoactivated during oral alcohol consumption that mice decrease their alcohol intake during DID. I also find that photoactivation does not induce real-time place preference, suggesting this circuitry is not directly modulating valence states, but may be altering encoding and expression of habitual actions, both well-defined striatal-based behaviors known to be altered by alcohol exposure. Together, these data suggest that the AIC plays a more expansive and diverse role in the addiction cycle beyond the preoccupation/anticipation stage than previously thought, but more work must be done to characterize alcohol-mediated AIC-DLS circuit changes. Aim 1 aims to identify how AIC→DLS circuitry is altered by alcohol exposure and how modulating AIC→DLS circuits can alter binge drinking behaviors. Aim 2 focuses on investigating how AIC→DLS circuits effect downstream medium spiny projection neuron activity to modulate striatal-based behaviors such as habitual responding in both alcohol naïve and alcohol exposed animals. Together, these data not only support an expanded role for the AIC as a key mediator of neuroadaptations in AUD beyond the preoccupation/anticipation stage, but also elucidates behavioral sequences governed by novel alcohol sensitive circuitry.