Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring
Gestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring
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DOI：
10.1038/s41467-020-16385-4
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发表时间：
2020-05-22
影响因子：
16.6
通讯作者：
Lovinger, David M.
中科院分区：
文献类型：
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作者：
Carlson, Verginia C. Cuzon;Gremel, Christina M.;Lovinger, David M.
胎儿酒精暴露（FAE）是认知功能障碍的主要可预防的发育原因。即使没有酗酒，怀孕期间饮酒也会导致后代缺陷。然而，这些缺陷的机制尚不清楚。使用妊娠期乙醇暴露（GEE）的小鼠模型，我们发现成年人的工具性压迫和有效习惯性行为的中断增加，表明认知功能中断。在体内电生理学揭示了与改变的习惯学习相关的背外侧纹状体（DLS）的行为编码中断。GEE小鼠表现出减少的GABA能传递到DLS投射神经元，包括来自小清蛋白中间神经元的输入，和增加的内源性大麻素张力。DLS小清蛋白中间神经元的化学发生激活降低了GEE小鼠升高的杠杆按压。药理学上增加内源性大麻素音调模仿GEE对认知和突触传递的影响。这些发现表明，GEE诱导认知功能的长期缺陷，这可能有助于人类FAE，并确定未来治疗靶向的潜在机制。酒精是美国可预防的出生缺陷的主要原因，统称为胎儿酒精谱系障碍。在这里，作者表明，胎儿酒精暴露诱导背侧纹状体持久的神经生理学变化，导致决策效率降低。
Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting. Alcohol is the leading cause of preventable birth defects in the US, collectively referred to as Fetal Alcohol Spectrum Disorder. Here, the authors show that fetal alcohol exposure induces lasting neurophysiological changes in dorsal striatum that contribute to less efficient decision making.