Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss.
Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss.
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甲基苯丙胺诱导的部分单胺丧失的大鼠中调节反应逆转学习和 Arc 介导的学习巩固的神经回路的变化。
DOI：
10.1038/npp.2013.296
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Keefe,KristenA
中科院分区：
文献类型：
--
作者：
Pastuzyn,ElissaD;Keefe,KristenA
甲基苯丙胺（METH）诱导的神经毒性导致单胺的长期消耗和基底神经节功能的变化。我们以前报道，大鼠与甲基苯丙胺诱导的神经毒性不再从事背内侧纹状体在反应逆转学习任务，因为他们的表现是不敏感的急性中断背内侧纹状体功能的局部输液的N-甲基-D-天冬氨酸受体拮抗剂或反义寡核苷酸对活性调节的细胞因子相关（弧）基因。然而，甲基苯丙胺预处理的大鼠执行任务以及控制。因此，我们假设，在METH预处理的大鼠中，参与学习的神经回路发生了变化。为了检验这一假设，大鼠预处理的神经毒性方案的甲基或生理盐水。3-5周后进行反向学习训练，并进行Arc原位杂交。在METH-，而不是盐水-，预处理大鼠的延髓核壳中发现Arc表达和任务性能之间的显着相关性。与Arc在大脑区域中的表达和行为表现之间的相关性暗示该大脑区域在学习中的想法一致，将针对Arc的反义寡核苷酸注入壳中损害了METH-而不是盐水-预处理大鼠中的逆转学习的巩固。这些发现提供了新的证据表明，甲基苯丙胺诱导的神经毒性导致从背侧到腹侧纹状体参与反向学习任务的转变。这种潜在的学习和记忆过程的神经回路的重组可能会导致METH诱导的神经毒性或其他纹状体多巴胺丢失的个体（如帕金森病患者）的认知功能受损。
Methamphetamine (METH)-induced neurotoxicity results in long-lasting depletions of monoamines and changes in basal ganglia function. We previously reported that rats with METH-induced neurotoxicity no longer engage dorsomedial striatum during a response-reversal learning task, as their performance is insensitive to acute disruption of dorsomedial striatal function by local infusion of an N-methyl-D-aspartate receptor antagonist or an antisense oligonucleotide against the activity-regulated cytoskeleton-associated (Arc) gene. However, METH-pretreated rats perform the task as well as controls. Therefore, we hypothesized that the neural circuitry involved in the learning had changed in METH-pretreated rats. To test this hypothesis, rats were pretreated with a neurotoxic regimen of METH or with saline. After 3–5 weeks, rats were trained on the reversal-learning task and in situ hybridization for Arc was performed. A significant correlation between Arc expression and performance on the task was found in nucleus accumbens shell of METH-, but not saline-, pretreated rats. Consistent with the idea that the correlation between Arc expression in a brain region and behavioral performance implicates that brain region in the learning, infusion of an antisense oligonucleotide against Arc into the shell impaired consolidation of reversal learning in METH-, but not saline-, pretreated rats. These findings provide novel evidence suggesting that METH-induced neurotoxicity leads to a shift from dorsal to ventral striatal involvement in the reversal-learning task. Such reorganization of neural circuitry underlying learning and memory processes may contribute to impaired cognitive function in individuals with METH-induced neurotoxicity or others with striatal dopamine loss, such as patients with Parkinson’s disease.