Knockdown of Nurr1 in the rat hippocampus: Implications to spatial discrimination learning and memory

Abstract

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.Learning requires the continued ability of the brain to establish new synaptic configurations and could be viewed as the continuation of the developmental process. Nurr1 (also known as HZF-3) (Peña de Ortiz and Jamieson Jr. 1996; Peña de Ge et al. 2003) is a member of the inducible nuclear receptor family of transcription factors (Law et al. 1992;Xing et al. 1997;Honkaniemi and Sharp 1999;Wang et al. 2003) that has been shown to play a key role in neural development. Specifically, expression of nurr1 is critical for the development of mesencephalic dopaminergic precursor neurons (Zetterstrom et al. 1997;Castillo et al. 1998;Saucedo-Cardenas et al. 1998 On the other hand, recent studies showed that nurr1 mutant heterozygous mice subjected to post-weaning isolation display a disruption of prepulse inhibition (a model of sensorimotor gating in the brain that is disrupted in patients with schizophrenia) (for review, see Van den Buuse et al. 2003), which is possibly related to decreased dopamine neurotransmission in the mutant heterozygous genotype (Eells et al. 2006). Disordered cognitive processes stemming from impaired hippocampal function are an important part of the positive symptoms in schizophrenia (Harvey et al. 2001;Antonova et al. 2004;Sweatt 2004;Johnson 2005). The holeboard spatial discrimination task was initially developed to study thought disorders in animal models of schizophrenia (Oades and Isaacson 1978). In this hippocampal-dependent task (Oades 1981), animals learn to discriminate between relevant versus irrelevant stimuli, a cognitive process that is impaired in schizophrenia (Gray and Snowden 2005). Our previous studies showed increased rat hippocampal nurr1 mRNA levels after the first and thi...

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors

“…Thus, Nr4a expression may be an important part of a CREB-initiated cascade of gene expression that contributes to the formation of long-term memory. This hypothesis is supported by existing data suggesting a role for Nr4a2 in long-term memory formation (11,21). In other biological contexts, Nr4a family members have been observed to have redundant functions (25,26).…”

“…Consistent with our results, in situ analysis has previously shown that Nr4a1 expression increases in hippocampal area CA1 (19) and that Nr4a2 expression increases in hippocampal areas CA1 and CA3 (20) following hippocampus-dependent learning. Additionally, Nr4a2 heterozygous null mice have impaired hippocampus-dependent passive avoidance memory (11), and Nr4a2 knockdown using antisense oligodeoxynucleotide injection into the hippocampus impairs long-term memory in a spatial discrimination task (21). Further, improved long-term spatial memory performance observed by deletion of HDAC3 in the hippocampus is attenuated by treatment with siRNA targeting Nr4a2 (22).…”

Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation

“…normal cognitive processes (38,39). Collectively, the transcriptional profile would have supported a more robust cognitive learning in irradiated KO mice.…”

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

“…Nr4a1 is expressed in the hippocampus after contextual fear conditioning (von Hertzen and Giese, 2005b;Keeley et al, 2006), and Nr4a2 is involved in learning of a spatial discrimination task (de Ortiz et al, 2000;Colon-Cesario et al, 2007). Nr4a1 and Nr4a2 may function in memory consolidation to activate secondary waves of transcription.…”