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

项目总结 超过1400万美国人目前患有酒精使用障碍(AUD)，尽管几十年来对 酒精对大脑的影响。减轻澳元负担的一个主要障碍是了解如何 神经系统功能障碍会导致酒精成瘾的发展和维持。要扩大规模 我们对AUD的理解，我们必须研究新的大脑区域和神经回路，并直接探测它们 用酒精攻击目标。最近感兴趣的大脑区域，岛叶(岛叶皮质)，已经被严重牵连到 成瘾循环的全神贯注/期待阶段。先前对人类的一项研究表明，吸烟者 获得性脑岛损伤显示吸烟冲动减少，这是脑岛在 成瘾周期的全神贯注/期待阶段。然而，有新的证据表明，岛上有一个 在成瘾周期的其他阶段发挥更大的作用。因此，迫切需要研究岛状电路。 以扩大我们对与AUD相关的神经适应的理解。最近，我们实验室发现了一种 前岛叶皮质(AIC)和背外侧纹状体(DLS)之间的联系，建立了 这个回路对酒精特别敏感。虽然我们知道AIC-DLS电路功能显示出酒精敏感性， 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 当以通道视紫红质(Chr)为靶点并进行光激活时，到dls的aic输入(aic→dls) 在口服饮酒期间，小鼠减少了在DID期间的酒精摄入量。我还发现， 光激活不会诱导实时位置偏爱，这表明这一电路不是直接调制的 配价状态，但可能改变习惯动作的编码和表达，两者都是基于纹状体的明确定义 已知的行为会因酒精暴露而改变。总而言之，这些数据表明AIC扮演着更重要的角色 在成瘾循环中的广泛和多样化的作用超越了关注/期待阶段 认为，但还需要做更多的工作来表征酒精介导的AIC-DLS电路变化。目标1旨在 确定酒精暴露如何改变AIC→DLS电路，以及调制AIC→DLS电路会如何改变 酗酒行为。目标2重点调查AIC→DLS电路对下行介质的影响 棘突投射神经元活动调节基于纹状体的行为，如在两种酒精中的习惯性反应 幼稚和酒精暴露的动物。总而言之，这些数据不仅支持AIC作为 注意力/期待阶段以外的AUD神经适应的关键调节因子，但也阐明 由新的酒精敏感电路控制的行为序列。

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.