Maroteaux Matthieu, Valjent Emmanuel, Longueville Sophie, Topilko Piotr, Girault Jean-Antoine, Hervé Denis
Inserm UMR-S 839, Paris, France ; Université Pierre et Marie Curie, Paris, France ; Institut du Fer à Moulin, Paris, France.
Inserm UMR-S 661, Montpellier, France ; UMR 5203 CNRS, Montpellier, France ; Université Montpellier I & II, Montpellier, France.
PLoS One. 2014 Jan 23;9(1):e81868. doi: 10.1371/journal.pone.0081868. eCollection 2014.
Gene transcription is essential for learning, but the precise role of transcription factors that control expression of many other genes in specific learning paradigms is yet poorly understood. Zif268 (Krox24/Egr-1) is a transcription factor and an immediate-early gene associated with memory consolidation and reconsolidation, and induced in the striatum after addictive drugs exposure. In contrast, very little is known about its physiological role at early stages of operant learning. We investigated the role of Zif268 in operant conditioning for food. Zif268 expression was increased in all regions of the dorsal striatum and nucleus accumbens in mice subjected to the first session of operant conditioning. In contrast, Zif268 increase in the dorsomedial caudate-putamen and nucleus accumbens core was not detected in yoked mice passively receiving the food reward. This indicates that Zif268 induction in these structures is linked to experiencing or learning contingency, but not to reward delivery. When the task was learned (5 sessions), Zif268 induction disappeared in the nucleus accumbens and decreased in the medial caudate-putamen, whereas it remained high in the lateral caudate-putamen, previously implicated in habit formation. In transgenic mice expressing green fluorescent protein (GFP) in the striatonigral neurons, Zif268 induction occured after the first training session in both GFP-positive and negative neurons indicating an enhanced Zif268 expression in both striatonigral and striatopallidal neurons. Mutant mice lacking Zif268 expression obtained less rewards, but displayed a normal discrimination between reinforced and non-reinforced targets, and an unaltered approach to food delivery box. In addition, their motivation to obtain food rewards, evaluated in a progressive ratio schedule, was blunted. In conclusion, Zif268 participates in the processes underlying performance and motivation to execute food-conditioned instrumental task.
基因转录对学习至关重要，但在特定学习范式中控制许多其他基因表达的转录因子的确切作用仍知之甚少。Zif268（Krox24/Egr-1）是一种转录因子，是与记忆巩固和再巩固相关的即早基因，在成瘾药物暴露后在纹状体中被诱导表达。相比之下，关于其在操作性学习早期阶段的生理作用却知之甚少。我们研究了Zif268在食物操作性条件反射中的作用。在接受首次操作性条件反射训练的小鼠中，背侧纹状体和伏隔核的所有区域中Zif268的表达均增加。相比之下，在被动接受食物奖励的配对小鼠中，未检测到背内侧尾状核 - 壳核和伏隔核核心区域的Zif268增加。这表明这些结构中Zif268的诱导与经历或学习偶然性有关，而与奖励的给予无关。当任务被学会（5次训练）时，伏隔核中的Zif268诱导消失，内侧尾状核 - 壳核中的Zif268减少，而在先前与习惯形成有关的外侧尾状核 - 壳核中其表达仍保持高水平。在纹状体黑质神经元中表达绿色荧光蛋白（GFP）的转基因小鼠中，在首次训练后，GFP阳性和阴性神经元中均出现Zif268诱导，表明纹状体黑质和纹状体苍白球神经元中Zif268表达均增强。缺乏Zif268表达的突变小鼠获得的奖励较少，但在强化和非强化目标之间表现出正常的辨别能力，并且对食物投放盒的接近方式未改变。此外，在累进比率时间表中评估的它们获取食物奖励的动机减弱。总之，Zif268参与执行食物条件性工具任务的行为表现和动机形成的潜在过程。
