Brightwell Jennifer J, Smith Clayton A, Neve Rachael L, Colombo Paul J
Department of Pharmacology, Tulane University, New Orleans, LA 70112, USA.
Neurobiol Learn Mem. 2008 Jan;89(1):27-35. doi: 10.1016/j.nlm.2007.09.004. Epub 2007 Oct 31.
Extensive research has shown that the striatum is necessary for response learning. We reported previously that rats using a response strategy to solve a cross maze task showed sustained phosphorylation of striatal CREB [Colombo, P. J., Brightwell, J. J., & Countryman, R. A. (2003). Cognitive strategy-specific increases in phosphorylated cAMP response element-binding protein and c-Fos in the hippocampus and dorsal striatum. Journal of Neuroscience, 23(8), 3547-3554], a transcription factor implicated in long-term memory formation. In the current study, we used viral vector-mediated gene transfer to test the hypothesis that CREB function in the dorsolateral striatum is necessary for the formation of long-term memory for a response strategy. In addition, we tested the hypothesis that the striatum and the hippocampus interact in a cooperative or competitive manner during memory formation. CREB function was blocked in the dorsolateral striatum by overexpression of a mutant form of CREB in which Ser133 was replaced with Ala (HSV-mCREB). CREB function was increased or decreased in the dorsal hippocampus by overexpressing wild-type CREB (HSV-CREB) or mutant CREB. Rats were trained to make a consistent turning response in one session to a criterion of 9 out of 10 correct trials in a water version of the cross maze. Experimental subjects and controls were trained 3 days following infusion into the hippocampus or striatum and tested for memory of the strategy 6 days later. There were no significant differences between treatment groups in acquisition of the task. At test, controls showed significant savings whereas rats infused with HSV-mCREB in the striatum did not. Rats receiving intrahippocampal overexpression of HSV-CREB, HSV-mCREB, or vehicle all showed significant savings between training and test. The present results show that long-term memory of a response strategy requires CREB function in the dorsolateral striatum and is independent of CREB function in the dorsal hippocampus.
大量研究表明，纹状体是反应学习所必需的。我们之前报道过，采用反应策略解决十字迷宫任务的大鼠，其纹状体中的CREB呈现持续磷酸化状态[科伦坡，P. J.，布赖特韦尔，J. J.，& 康特里曼，R. A.（2003年）。认知策略特异性地增加海马体和背侧纹状体中磷酸化的环磷酸腺苷反应元件结合蛋白及c-Fos。《神经科学杂志》，23(8)，3547 - 3554]，CREB是一种与长期记忆形成有关的转录因子。在当前研究中，我们使用病毒载体介导的基因转移来检验以下假设：背外侧纹状体中的CREB功能对于反应策略的长期记忆形成是必需的。此外，我们还检验了以下假设：在记忆形成过程中，纹状体和海马体以协同或竞争的方式相互作用。通过过表达一种将Ser133替换为Ala的突变形式的CREB（单纯疱疹病毒 - mCREB），可阻断背外侧纹状体中的CREB功能。通过过表达野生型CREB（单纯疱疹病毒 - CREB）或突变型CREB，可增强或降低背侧海马体中的CREB功能。训练大鼠在水迷宫版本的十字迷宫中进行一次持续的转向反应，达到10次正确试验中有9次正确的标准。实验对象和对照组在注入海马体或纹状体3天后接受训练，并在6天后测试其对策略的记忆。各治疗组在任务习得方面没有显著差异。在测试时，对照组表现出明显的节省效应，而在纹状体中注入单纯疱疹病毒 - mCREB的大鼠则没有。接受海马体内过表达单纯疱疹病毒 - CREB、单纯疱疹病毒 - mCREB或载体的大鼠在训练和测试之间均表现出明显的节省效应。目前的结果表明，反应策略的长期记忆需要背外侧纹状体中的CREB功能，且与背侧海马体中的CREB功能无关。
