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Role of Orphan Nuclear Receptor Nurr1 in Fear Conditioning

孤儿核受体 Nurr1 在恐惧调节中的作用

基本信息

批准号：
7408269
负责人：
JONATHAN E PLOSKI
金额：
$ 5.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2008-09-29
项目状态：
已结题

项目摘要

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.

描述（由候选人提供）：焦虑症是美国最常见的精神疾病，影响了1910万（13.3%）成年人口。获得性恐惧是许多焦虑症的根源，包括创伤后应激障碍（PTSD），旨在确定参与恐惧学习的新基因的研究可能会为这些疾病带来更有效的治疗方法。巴甫洛夫恐惧条件反射（英语：Pavlovian fear conditioning）是恐惧学习的一种形式，涉及杏仁核（英语：lateral nucleus of the amygdala）中条件刺激（CS）和非条件刺激（US）的感觉信息的整合，其中通过LTP样过程的突触传递的改变被认为编码记忆的关键方面。与大多数已研究的记忆形式一样，已知恐惧条件反射的长期记忆（LTM）形成需要转录因子cAMP-反应元件结合蛋白（CREB），其诱导早期反应基因的表达并间接诱导晚期反应基因，这些基因被认为对长期突触可塑性和记忆形成下的功能和/或结构变化至关重要。虽然许多CREB反应基因已被确定，但仍不清楚这些基因中有多少是恐惧学习所必需的。此外，许多可能参与LTM形成的CREB应答基因本身是转录因子，具有无数尚未鉴定的下游基因，这些基因可能是LTM形成所必需的。本提案的目标是确定CREB反应孤儿核受体Nurr 1（NR 4A 2，HZF- 3，NOT，RNR 1）在巴甫洛夫恐惧条件反射中的作用。我们的初步实验表明，Nurr 1的调节在一个联想的方式后恐惧学习。在这个建议中，我们试图了解Nurr 1是否是强制性的恐惧记忆的形成，以及确定新的下游目标，这CREB调节转录因子，可能有助于形成恐惧记忆的LA。以下具体目标将得到解决：目标一：是Nurr 1所需的巴甫洛夫恐惧条件反射？在这一目标中，我们将问是否Nurr 1所需的巴甫洛夫恐惧条件反射的记忆形成敲下Nurr 1基因的表达，使用腺相关病毒传递到杏仁核神经元的siRNA。目的二：巴甫洛夫恐惧条件反射调控Nurr 1的直接或间接下游靶点是什么？在这里，我们将对来自恐惧条件动物的杏仁核组织与来自恐惧条件动物的杏仁核组织进行微阵列基因表达分析，其中由于AAV-siRNA（Nurr 1）表达，Nurr 1表达已经被消除。这项研究将为确定新的CREB介导的基因表达在LA的目标，并检查他们在恐惧记忆形成的作用奠定基础。