Role of the Orphan Nuclear Receptor Nurr1 in Long Term Memory of Context Fear Conditioning

Abstract

Learning requires the continued ability of the brain to establish new synaptic configurations and could be viewed as the continuation of the developmental process. Disrupting the normal balance between the stable fixation of memory representations, via the establishment of strong synaptic connections, and the generation of new potential presynaptic and postsynaptic sites for use in future learning experiences could explain the clinical manifestations seen in several neuropsychiatric disorders such as, schizophrenia, as well as neurodevelopmental disorders such as autism. In the present research study we used Pavlovian fear processing, including acquisition and consolidation, to study the role of Nurr1, a member of the inducible nuclear receptor family of transcription factors that has been shown to play a key role in neural development and is associated to learning and memory. Nurr1 is an immediate early gene that can be induced by a variety of stimuli and its expression is localized predominantly in the brain (Jones et al., 1993; Zetterstrom et al., 1996; Xing et al., 1997). Genetic targeting of the nurr1 gene results in neonatal lethality by halting important neurodevelopmental processes in the brain (Zetterstrom et al., 1997; Castillo et al., 1998; Saucedo-Cardenas et al., 1998; Baffi et al., 1999). Specifically, studies utilizing nurr1(-/-) mice have shown that expression of Nurr1 is critical for the differentiation of mesencephalic dopaminergic precursor neurons during the late stages of embryonic brain development. Thus, nurr1 has been implicated in the pathogenesis or pathophysiology of dopamine-related neuropsychiatric conditions. Regulation of gene expression, at the levels of gene transcription and translation, has been shown to be pivotal for the formation of long-term memory (LTM). In addition, evidence obtained from different animal models and gene targeting approaches support the idea that transcriptional regulation by the cAMP Responsive Element Binding Protein (CREB) plays a role in LTM. In previous studies, our group was the first to establish, followed by findings by others (Ressler et al., 2002; Hawk et al 2012) that the expression of the gene encoding the immediate-early transcription factor nurr1 in the brain is subject to regulation of specific components related to cognitive processes (Peña de Ortiz et al., 2000; Al Baanchabuchi et al., 2004; Colón Cesario et al., 2006). Moreover, we have demonstrated that hippocampal knockdown of Nurr1 expression caused perseverative behavior reminiscent to that observed in schizophrenia, bipolar disorder, and obsessive compulsiveness (Colón-Cesario et al., 2006). Other groups have also found nurr1 expression (Ressler et al., 2002; Hawk et al., 2012) and function (Rojas et al., 2007; McNulty et al., 2012; and Hawk et al., 2012) is induced during and is relevant for learning and memory. In Chapter 2, we aimed at determining the role of Nurr1 in the hippocampus during acquisition and consolidation of context fear conditioning. Antisense oligonucleotides were shown to effectively reduce Nurr1 protein levels in vivo. In terms of cognitive processes, Nurr1 knockdown profoundly impaired long-term memory (LTM) after infusion into the CA3 hippocampal subregion in context fear conditioning. On the other hand, CA1 Nurr1 knockdown only caused moderate impairment in LTM. These results point to a functional dissociation of Nurr1 in the hippocampus. Finally, we also demonstrate that the subregional hippocampal dissociation of Nurr1 is under the transcriptional control of CREB. Overall, our results suggest that Nurr1 deficiency in learning and memory processes is necessary for the formation, development and maintenance of LTM and establish Nurr1 deficiency as a model for the cognitive disorders observed in neuropsychiatric disease.