Acute alcohol withdrawal is associated with c-Fos expression in the basal ganglia and associated circuitry: C57BL/6J and DBA/2J inbred mouse strain analyses
Acute alcohol withdrawal is associated with c-Fos expression in the basal ganglia and associated circuitry: C57BL/6J and DBA/2J inbred mouse strain analyses
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DOI：
10.1097/01.alc.0000187592.57853.12
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发表时间：
2005-11-01
影响因子：
3.2
通讯作者：
Buck, KJ
中科院分区：
文献类型：
--
作者：
Kozell, LB;Hitzemann, R;Buck, KJ
背景资料：DBA/2 J（D2）和C57 BL/6 J（B6）小鼠品系分别是研究最广泛的重度和轻度急性酒精戒断的遗传模型。先前的研究已经使用来自D2和B6菌株的作图群体确定了涉及急性乙醇戒断风险的数量性状位点和基因，但是这些基因及其蛋白产物影响乙醇生理依赖和相关戒断的脑区域和回路仍有待阐明。给予B6和D2镇静催眠剂量的乙醇（4 g/kg）或生理盐水（对照），并将其放回其饲养笼中，在那里它们静置7 h，这在先前的研究中已显示对应于急性乙醇戒断严重程度峰值。然后对小鼠实施安乐死，并评估其26个脑区的c-Fos免疫反应神经元数量。问题是是否乙醇戒断的D2和B6小鼠在c-Fos诱导方面存在差异（神经激活），可以解释D2品系小鼠的严重乙醇戒断和B6品系小鼠的轻度乙醇戒断。在急性乙醇戒断高峰期，D2和B6小鼠基底神经节内的神经激活不同，包括丘脑底核和基底神经节的两个主要输出核（内侧苍白球和黑质网状部）。基因型依赖的c-Fos诱导在相关的电路中也很明显，包括外侧隔，腹侧被盖区，背外侧尾壳核，黑质部，扣带和内嗅皮质，腹侧苍白球。D2和B6小鼠表现出相当的神经激活的床核的终纹，和nucleus benus shell.Conclusions：目前的研究是第一次使用立即早期基因产物的表达，以评估与急性乙醇戒断相关的神经激活的模式。我们的结果指出，延长的基底神经节回路参与了急性乙醇戒断的遗传决定差异。基于这些数据，我们认为，参与急性乙醇戒断的数量性状基因（QTG）通过一个或多个脑区和电路确定发挥其对这种表型的影响。随着越来越多的信息整合神经回路和QTG分析，QTG影响乙醇生理依赖和相关戒断的确切机制将变得明显。
Background: The DBA/2J (D2) and C57BL/6J (B6) mouse strains are the most widely studied genetic models of severe and mild acute alcohol withdrawal, respectively. Previous studies have identified quantitative trait loci and genes involved in risk for acute ethanol withdrawal using mapping populations derived from the D2 and B6 strains, but the brain region(s) and circuit(s) by which these genes and their protein products influence ethanol physiological dependence and associated withdrawal remain to be elucidated.Methods: B6 and D2 were administered a sedative-hypnotic dose of ethanol (4 g/kg) or saline (control) and returned to their home cages where they were left undisturbed for 7 hr, which has been shown in previous studies to correspond to peak acute ethanol withdrawal severity. The mice were then euthanized and assessed for their numbers of c-Fos immunoreactive neurons across 26 brain regions. The question addressed was whether or not ethanol-withdrawn D2 and B6 mice differed in c-Fos induction (neural activation) within circuitry that could explain the severe ethanol withdrawal of the D2 strain and the mild ethanol withdrawal in B6 strain mice.Results: At peak acute ethanol-withdrawal ethanol-withdrawn D2 and B6 mice differed in neural activation within the basal ganglia, including the subthalamic nucleus and the two major output nuclei of the basal ganglia (the medial globus pallidus and the substantia nigra pars reticulata). Genotype-dependent c-Fos induction was also apparent in associated circuitry including the lateral septum, the ventral tegmental area, the nucleus accumbens core, the dorsolateral caudate putamen, the substantia nigra pars compacta, the cingulate and entorhinal cortices, and the ventral pallidum. D2 and B6 mice showed comparable neural activation in the bed nucleus of the stria terminalis, and the nucleus accumbens shell.Conclusions: The present studies are the first to use immediate early gene product expression to assess the pattern of neural activation associated with acute ethanol withdrawal. Our results point to the involvement of an extended basal ganglia circuit in genetically determined differences in acute ethanol withdrawal. Based on these data, we suggest that quantitative trait genes (QTGs) involved in acute ethanol withdrawal exert their effects on this phenotype via one or more of the brain regions and circuits identified. As more information becomes available that integrates neural circuit and QTG analyses, the precise mechanisms by which QTGs affect ethanol physiological dependence and associated withdrawal will become apparent.