Synapse-specific interactions between ethanol and opioid receptor-mediated synaptic depression in dorsal striatum

项目概要 毫无疑问，酒精使用障碍 (AUD) 对美国造成了重大的社会经济损失 各国和世界其他地区。目前的许多治疗方法都不够有效，因为它们没有针对 神经行为基础有助于许多人酒精滥用的发展和维持 个人。迫切需要新的治疗干预措施来消除副作用 乙醇对大脑回路的影响，恢复对饮酒行为的认知控制。进步的障碍是缺乏 了解乙醇对已知的大脑部分内的选定突触的具体影响 控制与酒精相关的行为，甚至控制其中许多选择的突触在上下文中的行为作用 每个大脑区域的更大功能。我们的初步数据表明乙醇仅影响某些形式 阿片受体介导的突触可塑性在背侧纹状体内非常特定的突触处，同时离开 附近突触的可塑性不受影响。这些突触之一是来自前岛叶皮质的输入 （AIC）到背外侧纹状体（DLS）。 AIC 参与乙醇内感受，DLS 控制 对乙醇饮用和寻求行为的习惯性反应。小鼠体内乙醇暴露会破坏 mu 阿片类药物在此突触处产生长期突触抑制 (LTD)，同时在其他突触处保留 mu 阿片类信号传导 不受影响。由 kappa 和 delta 阿片受体介导的 LTD 发生在未识别的背侧纹状体突触处 乙醇对这些形式的 LTD 可能有类似的不同影响。我们的数据还显示 AIC-DLS 的 LTD 突触可能是由 cAMP 信号传导和蛋白质从头合成改变介导的。此举的目的 提议是确定突触特异性阿片类药物LTD机制以及乙醇如何选择性地影响某些 突触，同时不影响其他突触，并确定 AIC-DLS 中阿片类药物 LTD 的行为相关性 突触。我们的中心假设是，酒精会破坏特定突触的背侧纹状体阿片类药物的可塑性 突触处独特的酒精敏感信号通路调节酒精消耗、寻找和饮酒 内感受。在目标 1 中，我们将确定体内乙醇暴露对 mu、delta 和 kappa 阿片类药物的影响 特定类型的背侧纹状体谷氨酸突触受体介导的突触抑制。在目标 2 中，我们将 确定背侧纹状体阿片可塑性的乙醇敏感和不敏感形式的机制 破译乙醇对这些信号通路的影响。在目标 3 中，我们将解密 mu 阿片类药物 LTD 的作用 AIC-DLS 突触在乙醇消耗、寻找和内感受方面的作用。我们将使用脑切片 电生理学、体外和体内光遗传学、转基因小鼠、病毒载体和药理学工具 解决这三个目标。通过了解乙醇对可塑性机制的突触特异性影响 背侧纹状体中行为定义的突触，我们将确定治疗 AUD 的新治疗靶点。 这将是改善受澳元影响的人们生活的一个飞跃。

Project Summary There is no doubt that the alcohol use disorders (AUDs) have a significant socioeconomic toll on the United States and the rest of the world. Many current therapeutics are not sufficiently effective, as they do not target the neurobehavioral underpinnings contributing to the development and maintenance of alcohol abuse in many individuals. There is a critical need for novel therapeutic interventions that can undo the negative effects of ethanol on brain circuitry, restoring cognitive control over drinking behavior. A barrier to progress is a lack of understanding of the specific effects that ethanol has on select synapses within parts of the brain known to control alcohol-related behaviors and even the behavioral role of many of these select synapses in the context of the larger function of each brain region. Our preliminary data indicate that ethanol only affects certain forms of opioid receptor-mediated synaptic plasticity at very specific synapses within the dorsal striatum while leaving plasticity at nearby synapses unaffected. One of these synapses is the inputs from the anterior insular cortex (AIC) to the dorsolateral striatum (DLS). The AIC is involved in ethanol interoception and the DLS controls habitual responding for ethanol drinking and seeking behavior. In vivo ethanol exposure in mice disrupts mu opioid long-term synaptic depression (LTD) at this synapse while leaving mu opioid signaling at other synapses unaffected. LTD mediated by kappa and delta opioid receptors occur at unidentified dorsal striatal synapses and ethanol could have similar differential effects on these forms of LTD. Our data also show that LTD at AIC-DLS synapses is likely mediated by altered cAMP signaling and de novo protein synthesis. The objective of this proposal is to determine synapse-specific opioid LTD mechanisms and how ethanol selectively affects some synapses, while leaving others unaffected and to determine the behavioral relevance of opioid LTD at AIC-DLS synapses. Our central hypothesis is that alcohol disrupts dorsal striatal opioid plasticity at specific synapses due to distinct alcohol-sensitive signaling pathways at synapses that modulate alcohol consumption, seeking, and interoception. In Aim 1, we will identify the impact of in vivo ethanol exposure on mu, delta, and kappa opioid receptor-mediated synaptic depression at specific types of dorsal striatal glutamatergic synapses. In Aim 2 we will determine the mechanisms of ethanol-sensitive and insensitive forms of dorsal striatal opioid plasticity to decipher the impact of ethanol on these signaling pathways. In Aim 3 we will decipher the role of mu opioid LTD at AIC-DLS synapses in ethanol consumption, seeking, and interoception. We will use brain slice electrophysiology, in vitro and in vivo optogenetics, transgenic mice, viral vectors, and pharmacological tools to address these three aims. By understanding the synapse-specific effects of ethanol on plasticity mechanisms at behaviorally-defined synapses in the dorsal striatum, we will identify novel therapeutic targets for treating AUDs. This will be a leap forward towards improving the lives of those that suffer from the effects of AUDs.