Role of Orphan Nuclear Receptor Nurr1 in Fear Conditioning

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DESCRIPTION (provided by candidate): Anxiety disorders are the most common mental illness in the U.S., affecting 19.1 million (13.3%) of the adult population. Acquired fears are at the root of many anxiety disorders, including post-traumatic stress disorder (PTSD), and studies aimed at identifying novel genes involved in fear learning may lead to more effective treatments for these disorders. Pavlovian fear conditioning is a form of fear learning that involves integration of sensory information about the conditioned stimulus (CS) and unconditioned stimulus (US) in the lateral nucleus of the amygdala (LA), where alterations in synaptic transmission via an LTP-like process are thought to encode key aspects of the memory. Like most forms of memory that have been studied, long-term memory (LTM) formation of fear conditioning is known to require the transcription factor cAMP- response-element binding protein (CREB), which induces the expression of early response genes and indirectly induces late response genes that are thought to be critical for the functional and/or structural changes underling long-term synaptic plasticity and memory formation. Although many CREB responsive genes have been identified, it remains unclear how many of these genes are required for fear learning. In addition many CREB responsive genes likely to be involved in LTM formation are themselves transcription factors with countless yet unidentified downstream genes likely necessary for LTM formation. The goal of this proposal is to determine the role of the CREB responsive orphan nuclear receptor Nurr1 (NR4A2, HZF- 3, NOT, RNR1) in Pavlovian fear conditioning. Our preliminary experiments indicate that Nurr1 is regulated in an associative manner following fear learning. In this proposal, we seek to understand whether Nurr1 is obligatory for fear memory formation as well as to identify novel downstream targets of this CREB-regulated transcription factor that may contribute to formation of fear memories in the LA. The following Specific Aims will be addressed: Aim I: Is Nurr1 required for Pavlovian fear conditioning? In this aim, we will ask whether Nurr1 is required for memory formation of Pavlovian fear conditioning by knocking down Nurr1 gene expression using siRNA delivered to amygdala neurons using adeno-associated virus. Aim II: What are the direct or indirect downstream targets of Nurr1 regulated by Pavlovian fear conditioning? Here, we will perform microarray gene expression analysis on amygdala tissue from fear conditioned animals versus amygdala tissue from fear conditioned animals where Nurr1 expression has been ablated due to AAV- siRNA (Nurr1) expression. The studies outlined in this proposal will lay the groundwork for identifying novel targets of CREB-mediated gene expression in the LA and for examining their role in fear memory formation.