Chronic alcohol produces neuroadaptations to prime dorsal striatal learning
Chronic alcohol produces neuroadaptations to prime dorsal striatal learning
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DOI：
10.1073/pnas.1308198110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Holmes, Andrew
中科院分区：
文献类型：
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作者：
DePoy, Lauren;Daut, Rachel;Holmes, Andrew
包括酗酒在内的药物成瘾的特征是对行为的执行控制能力下降和强迫性寻求药物的增加。据推测，这些深刻的行为变化涉及行为调节从前额皮质到背侧纹状体（DLS）的转变。对啮齿类动物的研究表明，乙醇会破坏前额皮质介导的认知过程，但长期乙醇对 DLS 介导的认知和学习的潜在影响尚不清楚。在这里，我们首先检查了慢性 EtOH 对 DLS 神经元形态、突触可塑性和内源性大麻素-CB1R 信号传导的影响。接下来，我们测试了乙醇诱导的纹状体相关学习变化和学习过程中 DLS 体内单单元活动。暴露于慢性间歇性乙醇 (CIE) 蒸汽的小鼠在 DLS 神经元中表现出树突状物质的扩张。 CIE 后，DLS 内源性大麻素 CB1 受体信号传导下调，并且 DLS 突触处不存在 CB1 受体依赖性长期抑制。相对于暴露在空气中的对照组，CIE 小鼠表现出依赖 DLS 的成对视觉辨别和逆转学习的促进作用。在忽略计划下，CIE 小鼠也能更快地消除刺激奖励工具反应，并更快地减少巴甫洛夫趋近行为。学习过程中的体内单单元记录显示，CIE 小鼠在正确反应期间增强了 DLS 神经元活动。总的来说，这些发现支持了一个模型，即长期乙醇会导致 DLS 中的神经适应，从而为 DLS 更好地控制学习做好准备。向纹状体主导行为的转变可能是酗酒进展的关键一步。
Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.