The Role of NR4A1 and NR4A2 in Long-Term Memory Formation

Long-term memory (LTM) requires transcription, a process in which CREB (cAMP response element-binding) is essential. CREB regulates NR4A1 (nerve growth factor IB) and NR4A2 (nuclear receptor related 1 protein); transcription factors belonging to the orphan nuclear receptor family. NR4A1 and NR4A2 have been implicated in memory formation, however, little is known of their direct contribution to learning and memory. We hypothesize that expression of NR4A1 and NR4A2 is critical for specific forms of long-term memory in the hippocampus and cortex. To test this we performed immunohistochemistry on coronal slices and observed that NR4A1 and NR4A2 expression in the CA1 of the hippocampus increased by 40% following a learning event. Infusing siRNA in the hippocampus, we sought to observe the effect of the knockdown of NR4A1 and NR4A2 expression in learning and memory. We observed that when either hippocampal NR4A1 or NR4A2 expression decreased, memory for location, a hippocampus-dependent task, was impaired as measured by an object location memory test. Comparatively, when investigating the cortical regions we found NR4A2 expression, but not NR4A1, within cortical layer VI.  We saw that NR4A2 coupled with the neuronal marker NeuN co-localized in layer VI neuronal cells. In addition, cortical NR4A2 doubled after training. To observe the effect of the knockdown of NR4A1 and NR4A2 in the cortex, we infused siRNA into the ventricles. NR4A2 expression decreased, and consequently it was observed that the memory for recognition of the object, a cortex-dependent task, was impaired. On the other hand, NR4A1 expression remained the same and no impairment of memory was seen. The results indicate that hippocampal NR4A1 and NR4A2 are necessary for long-term memory of object location, while cortical NR4A2 is required for object recognition long-term memory. In conclusion, NR4A1 and NR4A2 expression in the hippocampus and NR4A2’s expression in the cortical regions is necessary for long-term memory. Supported by the MARC NIH Grant GM-69337.