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

项目摘要 毫无疑问，酒精使用障碍（AUD）对美国的社会经济造成了重大影响。 国家和世界其他地区。许多目前的治疗剂不是足够有效的，因为它们不靶向肿瘤细胞。 神经行为基础有助于发展和维持酒精滥用在许多 个体迫切需要新的治疗干预措施，可以消除的负面影响， 酒精对大脑回路的影响，恢复对饮酒行为的认知控制。进步的障碍是缺乏 了解乙醇对大脑已知部分内选择突触的具体影响， 控制与酒精相关的行为，甚至控制许多这些选择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，乙醇只影响某些形式， 阿片受体介导的突触可塑性在背侧纹状体内非常特殊的突触，而离开 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层的输入 (AIC)背外侧纹状体（dorsolateral striatum，DLS）AIC参与乙醇内感受和DLS对照 习惯性饮酒反应和寻求行为。小鼠体内乙醇暴露破坏了小鼠 阿片样物质长期突触抑制（LTD）在这个突触，而留下μ阿片样物质信号在其他突触 不受影响由κ和δ阿片受体介导的LTD发生在未识别的背侧纹状体突触， 乙醇可能对这些形式的LTD有类似的不同影响。我们的数据还表明，在AIC-DLS的LTD 突触可能通过改变的cAMP信号传导和从头蛋白质合成来介导。的目的 一项建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一些 突触，而其他突触不受影响，并确定阿片类药物LTD在AIC-DLS的行为相关性 突触我们的中心假设是，酒精破坏了特定突触的背侧纹状体阿片可塑性， 突触上不同的酒精敏感信号通路调节酒精消耗，寻求， 内感受。在目标1中，我们将确定体内乙醇暴露对μ，δ和κ阿片类药物的影响。 受体介导的突触抑制在特定类型的背侧纹状体神经元突触。在目标2中， 确定乙醇敏感和不敏感形式的背侧纹状体阿片可塑性的机制， 解读乙醇对这些信号通路的影响。在目标3中，我们将破译μ阿片LTD的作用， 在酒精消耗、寻求和内感受中的AIC-DLS突触。我们会用脑切片 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， 实现这三个目标。通过了解乙醇对可塑性机制的突触特异性作用， 行为定义的突触在背侧纹状体，我们将确定新的治疗目标，用于治疗AUD。 这将是改善那些遭受AUD影响的人的生活的一个飞跃。

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.