Transfection of mutant CREB in the striatum, but not the hippocampus, impairs long-term memory for response learning

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.