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)对美国人造成了重大的社会经济损失 美国和世界其他地区。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，以消除 酒精对大脑回路的影响，恢复了对饮酒行为的认知控制。进步的一个障碍是缺乏 了解乙醇对大脑已知部分的特定突触的特定影响 控制与酒精相关的行为，甚至控制许多这些精选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的 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上 附近突触的可塑性未受影响。其中一个突触是来自前岛叶皮质的输入 (AIC)至背外侧纹状体(DLS)。AIC参与酒精内感和DLS控制 对饮酒和寻觅行为的习惯性反应。小鼠体内酒精暴露可扰乱MU 阿片类药物在该突触的长期突触抑制(LTD)，同时在其他突触留下u阿片信号 不受影响。LTD由Kappa和Delta阿片受体介导，发生在不明原因的背侧纹状体突触和 乙醇对这些形式的LTD可能有类似的差异效应。我们的数据还显示，AIC-DLS的有限公司 突触可能是通过改变cAMP信号和从头合成蛋白质来调节的。这样做的目的是 建议确定突触特定的阿片类药物有限公司的机制，以及乙醇如何选择性地影响一些 突触，而其他不受影响，并确定阿片类药物有限公司在AIC-DLS的行为相关性 突触。我们的中心假设是酒精扰乱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，调节酒精的消费、寻求和 内感。在目标1中，我们将确定体内酒精暴露对u、Delta和kappa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谷氨酸能突触。在《目标2》中我们将 确定酒精敏感和不敏感形式的背侧纹状体阿片可塑性对 破译乙醇对这些信号通路的影响。在目标3中，我们将破译Mu阿片有限公司的角色 在酒精消费、寻求和内感中的AIC-DLS突触。我们将使用脑片 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。通过了解乙醇对突触特异性可塑性机制的影响 行为定义的突触在背侧纹状体，我们将确定治疗AUDS的新治疗靶点。 这将是朝着改善那些遭受AUDS影响的人的生活迈出的一大步。

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.