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...

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