Differential roles for Nr4a1 and Nr4a2 in object location vs. object recognition long-term memory

Abstract

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 ...

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

“…cFos was significantly increased in the DH after fear conditioning (one-way ANOVA, F (2,26) = 23.3, po0.001), with significantly higher expression at 30 min (Sidak post hoc, po0.001) and 60 min (po0.001) relative to homecage controls ( Figure 1b). We also measured Nr4a2, which is both CREB-dependent (Conkright et al, 2003;McNulty et al, 2012;Vecsey et al, 2007) and regulated by HDAC3 . Nr4a2 was significantly increased after acquisition (F (2,26) = 7.8, po0.01), with significantly higher expression 30 min after conditioning (po0.01) and 60 min after learning (Figure 1c; po0.01).…”

Effects of glyceollin on mRNA expression in the female mouse brain.

“…Nr4a1 is moderately expressed in various hypothalamic nuclei (Saucedo-Cardenas and Conneely 1996). Nr4a1 is downregulated by E2 in the mouse hypothalamus (Lundholm et al 2008) and plays a functional role in stress responses (Helbling et al 2014), food intake (Chen et al 2015), and cognition (McNulty et al 2012). Nr4a1 is also highly expressed in the hippocampus, with highest expression in the CA1 region (McNulty et al 2012;Saucedo-Cardenas and Conneely 1996).…”

“…Nr4a1 is downregulated by E2 in the mouse hypothalamus (Lundholm et al 2008) and plays a functional role in stress responses (Helbling et al 2014), food intake (Chen et al 2015), and cognition (McNulty et al 2012). Nr4a1 is also highly expressed in the hippocampus, with highest expression in the CA1 region (McNulty et al 2012;Saucedo-Cardenas and Conneely 1996). Nr4a1 plays a role in memory formation (Hawk and Abel 2011), specifically object location memory (McNulty et al 2012).…”

“…Nr4a1 is also highly expressed in the hippocampus, with highest expression in the CA1 region (McNulty et al 2012;Saucedo-Cardenas and Conneely 1996). Nr4a1 plays a role in memory formation (Hawk and Abel 2011), specifically object location memory (McNulty et al 2012). Thus, it was not surprising to observe relatively higher Nr4a1 expression in the hippocampus, compared to the hypothalamus and cortex.…”

“…Thus, it was not surprising to observe relatively higher Nr4a1 expression in the hippocampus, compared to the hypothalamus and cortex. As it is an immediate early-response gene and is upregulated 2 hrs after object location memory training in the CA1 region of the mouse hippocampus (McNulty et al 2012), we expected that acute Gly (2hr, 24hr or 48hr), would increase Nr4a1 expression, especially in the hippocampus. However, in contrast to the microarray study, we did not detect significant upregulation of Nr4a1 expression by Gly in any of the brain regions tested, nor did we detect E2 downregulation of Nr4a1 in the hypothalamus.…”