Impact of stress on GluR2 transcription and learning-induced synaptic plasticity

压力对 GluR2 转录和学习诱导的突触可塑性的影响

基本信息

批准号：
8826180
负责人：
Siqiong June Liu
金额：
$ 35.5万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8826180
关键词：
AMPA Receptors Acute Adenylate Cyclase Affect Anxiety Disorders Ataxia Attenuated Binding Cerebellar Ataxia Cerebellum Cessation of life Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP-Responsive DNA-Binding Protein Development Disease Epigenetic Process Epilepsy Extinction (Psychology)Figs - dietary Functional disorder Gene Expression Gene Silencing Genes Genetic Genetic Transcription Glutamates Histone Acetylation Histones Hormones In Vitro Individual Interneuron function Interneurons Investigation Ischemia Learning Link Memory Mental Depression Mental disorders Messenger RNA Modification Motor Mus Neurologic Neurons Norepinephrine Output Pathway interactions Phenotype Post-Traumatic Stress Disorders Preparation Promoter Regions Purkinje Cells Recruitment Activity Role Signal Pathway Stress Synapses Synaptic Transmission Synaptic plasticity Testing Training Transcription Coactivator Transcription Repressor/Corepressor acute stress chromatin remodeling classical conditioning design in vivo information processing inhibitor/antagonist insight motor control motor disorder nervous system disorder new therapeutic target novel promoter protein activation receptor receptor expression research study stellate cell transcription factor

项目摘要

DESCRIPTION (provided by applicant): The cerebellum is critically involved in motor coordination and associative learning, both of which are regulated by stress. Stress can trigger cerebellar ataxia in susceptible individuals and also enhances associative learning. We have recently shown that noradrenaline released during an acute olfactory stress in mice promotes GluR2 gene transcription and alters excitatory synaptic transmission onto cerebellar inhibitory interneurons. In addition we found that this stress-induced increase in synaptic GluR2 expression has important consequences because it markedly enhances the activity of cerebellar stellate cells. These inhibitory interneurons alter Purkinje cell firing, and thereby control motor coordination and learning. Therefore we propose that stress enhances GluR2 gene transcription and consequently alters learning-induced synaptic plasticity. This provides a novel mechanism by which stress can regulate associative learning and memory. The primary objective in this proposal is to understand the mechanisms and functional consequences of this stress-induced transcriptional dependent switch. Our central hypothesis is that the stress hormone, noradrenaline, increases the number of synaptic GluR2-containing receptors via epigenetic remodeling of the GluR2 gene, thereby altering the synaptic plasticity that is induced by associative learning. The specific aims are: Aim 1. To determine the underlying mechanisms for the stress-induced increase in GluR2 gene transcription in stellate cells. We will examine the role of two transcriptional regulators. 1) The transcriptional activator CREB which promotes GluR2 transcription. We will test whether noradrenaline promotes GluR2 transcription via activation of cAMP/PKA/CREB signaling pathways. 2) The transcriptional repressor REST binds to the GluR2 promoter region and recruits histone deacetylases which can silence GluR2 gene expression. We test the hypothesis that stress acts via chromatin remodeling to increase GluR2 mRNA. Aim 2. To examine the consequences of a stress-induced enhancement of GluR2 transcription on learning-dependent synaptic plasticity. We will test the prediction that stress enhances associative learning-dependent synaptic plasticity and attenuates the extinction-induced reversal in stellate cells. The proposed study is designed to determine how a stress-induced change in interneuron functioning can alter the synaptic plasticity that is observed during learning. It may also provide insights into how stress can act as a trigger for cerebellar ataxias. Alterations in GluR2 gene transcription contribute to a number of neurological disorders, including stress-induced depression and ischemia-induced neuronal death. Findings from the proposed studies are relevant to our understanding of many stress-related neurological disorders.

描述（由申请人提供）：小脑对于运动协调和联想学习至关重要，这两者都受到压力的调节。压力会引发易感个体的小脑共济失调，并增强联想学习。我们最近发现，小鼠急性嗅觉应激期间释放的去甲肾上腺素可促进 GluR2 基因转录并改变小脑抑制性中间神经元的兴奋性突触传递。此外，我们发现这种应激诱导的突触 GluR2 表达增加具有重要的后果，因为它显着增强了小脑星状细胞的活性。这些抑制性中间神经元改变浦肯野细胞放电，从而控制运动协调和学习。因此，我们认为压力会增强 GluR2 基因转录，从而改变学习诱导的突触可塑性。这提供了一种新的机制，压力可以通过该机制调节联想学习和记忆。该提案的主要目标是了解这种应激诱导的转录依赖性开关的机制和功能后果。我们的中心假设是，应激激素去甲肾上腺素通过 GluR2 基因的表观遗传重塑增加含有 GluR2 的突触受体的数量，从而改变联想学习诱导的突触可塑性。具体目标是：目标 1. 确定星状细胞中应激诱导 GluR2 基因转录增加的潜在机制。我们将研究两个转录调节因子的作用。 1) 转录激活因子CREB，促进GluR2转录。我们将测试去甲肾上腺素是否通过激活 cAMP/PKA/CREB 信号通路来促进 GluR2 转录。 2) 转录抑制因子 REST 与 GluR2 启动子区域结合并招募组蛋白脱乙酰酶，从而沉默 GluR2 基因表达。我们测试了这样的假设：压力通过染色质重塑来增加 GluR2 mRNA。目标 2. 检查应激诱导的 GluR2 转录增强对学习依赖性突触可塑性的影响。我们将测试压力增强关联学习依赖性突触可塑性并减弱星状细胞中灭绝诱导的逆转的预测。拟议的研究旨在确定压力引起的中间神经元功能变化如何改变学习过程中观察到的突触可塑性。它还可能提供关于压力如何触发小脑共济失调的见解。 GluR2 基因转录的改变会导致许多神经系统疾病，包括应激引起的抑郁和缺血引起的神经元死亡。拟议研究的结果与我们对许多与压力相关的神经系统疾病的理解相关。