Nr4a1 and Nr4a2 are transcription factors and immediate early genes belonging to the nuclear receptor Nr4a family. In this study, we examine their role in long-term memory formation for object location and object recognition. Using siRNA to block expression of either Nr4a1 or Nr4a2, we found that Nr4a2 is necessary for both long-term memory for object location and object recognition. In contrast, Nr4a1 appears to be necessary only for object location. Indeed, their roles in these different types of long-term memory may be dependent on their expression in the brain, as NR4A2 was found to be expressed in hippocampal neurons (associated with object location memory) as well as in the insular and perirhinal cortex (associated with object recognition memory), whereas NR4A1 showed minimal neuronal expression in these cortical areas. These results begin to elucidate how NR4A1 and NR4A2 differentially contribute to object location versus object recognition memory.[Supplemental material is available for this article.]It is well established that long-term memory (LTM) formation requires transcription (for review, see Alberini 2009). Transcription regulated specifically by cAMP responsive element binding protein (CREB) has been shown to be essential for long-term memory (Bourtchuladze et al. 1994;Yin et al. 1994;Guzowski and McGaugh 1997;Pittenger et al. 2002;Sekeres et al. 2010; but see Balschun et al. 2003). Two CREB-dependent immediate early genes that have been implicated in LTM are Nr4a1 and Nr4a2 (Pena de Ortiz et al. 2000; von Hertzen and Giese 2005a,b;Colon-Cesario et al. 2006). Nr4a1 (Nur77) and Nr4a2 (Nurr1) are members of the nuclear steroid/thyroid hormone receptor superfamily that bind in an apparently ligand-independent manner to Nerve Growth Factor1-B (NGFI-B) response elements (Baker et al. 2003;Wang et al. 2003).Expression of both Nr4a1 and Nr4a2 has been shown to increase in the hippocampus following learning. Nr4a1 expression increased in the CA1 region of the hippocampus during context shock memory consolidation, and Nr4a2 increased in CA1 and CA3 pyramidal cell layers of the rat hippocampus following a spatial discrimination task (Pena de Ortiz et al. 2000; von Hertzen and Giese 2005a,b;Keeley et al. 2006;Hawk and Abel 2011). An exception to these findings was a study from Malkani and Rosen (2000) who found increased Nr4a1 expression in the cortex and amygdala following context shock memory consolidation, but failed to see a change in area CA1 of the hippocampus. These patterns of expression suggest a role for the Nr4a family in learning and memory.Transcription of both Nr4a1 and Nr4a2 appear to be regulated by chromatin modification via histone acetylation and deacetylation. Histone deacetylase (HDAC) activity was shown to interfere with formation of the pre-initiation complex at the Nr4a1 promoter, suggesting that acetylation is necessary for its transcription (Fass et al. 2003). In addition, during memory consolidation, the HDAC inhibitor Trichostatin A (TSA) maintained the expression of both Nr4a1 ...