Behavioral and Molecular Analysis of Chromatin Modifications in Memory Retrieval

记忆检索中染色质修饰的行为和分子分析

基本信息

批准号：
8465945
负责人：
James M Stafford
金额：
$ 4.22万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465945
关键词：
Address Affect Affective American Amygdaloid structure Anguish Anxiety Anxiety Disorders BDNF gene Back Behavior Behavioral Biological Assay Biological Neural Networks Brain Brain region Brain-Derived Neurotrophic Factor Chromatin Clinical Complex Cues DNA Packaging Data Diagnostic and Statistical Manual Emotional Exposure to Extinction (Psychology)Failure Fright Future Gene Expression Gene Targeting Generations Genes Genetic Transcription Goals Hippocampus (Brain)Histone Acetylation Histone Deacetylase Inhibitor Infusion procedures Intervention Knowledge Lead Learning Maintenance Maps Memory Modification Molecular Molecular Analysis Molecular Profiling Mus Neurobiology Outcome Pharmacologic Substance Post-Traumatic Stress Disorders Prefrontal Cortex Process Psyche structure Reaction Research Research Proposals Retrieval Shock Site Stimulus System Time Transcriptional Regulation Wood material chromatin modification conditioned fear conditioning experience insight interest memory acquisition memory retrieval novel prevent public health relevance relating to nervous system response therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Every year at least 18% of all Americans are afflicted with an anxiety disorder. Current treatment strategies for many anxiety disorders focus on ways to lessen the ability of environmental stimuli to evoke mental, emotional and physical anguish. One treatment is extinction - exposure to fear-evoking environmental stimuli in the absence of the aversive outcome can weaken the ability of those stimuli to elicit anxiety responses. Extinction results in the formation of a new inhibitory extinction memory that prevents the stimuli from reactivating such powerful affective responses and is thus an active process requiring accompanying changes in underlying neural networks. Recent research indicates that chromatin (DNA packaging complexes) modifications via histone acetylation (HA) results in networks of molecular changes (e.g., gene expression) underlying memory formation. Although many studies have shown that increasing HA with histone deacetylase inhibitors (HDACi) enhances learning, we know surprisingly little about how HDACi and changes in HA modulate fear memory extinction and reactivation. The major goals of this proposal are to bridge this gap in knowledge by (1) addressing how pharmacologically manipulating HA within neural networks alters fear reactivation and extinction, and (2) to assess how systems-wide changes in HA dependent gene expression map into behavioral expression of fear extinction and reactivation in mice. To establish a fearful memory, mice will receive contextual fear conditioning, in which exposure to a novel context will be paired with a shock. The memory will be reactivated at different post-conditioning time points by exposing mice to the context (memory retrieval). During these reactivation episodes, extinction will develop as the mice learn that the context is no longer associated with the shock (fear extinction). In Aim 1, we will evaluate how the time course of HDACi prior to memory retrieval affects 1) subsequent expression of the fear memory in behavior and 2) time-dependent regional changes in HA following memory retrieval. In Aim 2, we will examine the effects of HDACi infusion into different brain regions prior to a memory retrieval trial on (1) enhancements and extinction of behavior, and (2) effects on transcriptional control of regional gene expression following memory retrieval. By combining molecular, neuropharmacological and behavioral approaches, the proposed study aims to provide insight into molecular and neural systems that are potential therapeutic targets for decreasing the impact of traumatic and anxiety-inducing stimuli. PUBLIC HEALTH RELEVANCE: Many anxiety disorders, including post-traumatic stress disorder, are characterized by a failure to inhibit the powerful mental, emotional and physical anguish evoked by environmental stimuli. The proposed research aims to understand how brain region specific networks of genes are activated in response to these anxiety- inducing stimuli. By examining how these molecular changes map into fear-related behavior, this study will guide future research in devising pharmaceutical interventions for anxiety disorders that dampen the emotional impact of anxiety-inducing stimuli by targeting these gene networks.

描述（由申请人提供）：每年至少有 18% 的美国人患有焦虑症。目前许多焦虑症的治疗策略侧重于减少环境刺激引起精神、情感和身体痛苦的能力。一种治疗方法是消除——在没有厌恶结果的情况下暴露于引起恐惧的环境刺激可以削弱这些刺激引起焦虑反应的能力。消退会导致新的抑制性消退记忆的形成，从而防止刺激重新激活如此强大的情感反应，因此是一个主动过程，需要伴随基础神经网络的变化。最近的研究表明，通过组蛋白乙酰化 (HA) 进行的染色质（DNA 包装复合物）修饰会导致记忆形成过程中的分子变化（例如基因表达）网络。尽管许多研究表明，用组蛋白脱乙酰酶抑制剂 (HDACi) 增加 HA 可以增强学习能力，但令人惊讶的是，我们对 HDACi 和 HA 的变化如何调节恐惧记忆消退和重新激活知之甚少。该提案的主要目标是通过以下方式弥合这一知识差距：（1）解决神经网络内的药理操纵HA如何改变恐惧重新激活和消退，以及（2）评估HA依赖性基因表达的全系统变化如何映射到行为小鼠恐惧消退和重新激活的表达。为了建立恐惧记忆，小鼠将接受情境恐惧调节，其中暴露于新的情境将与电击相结合。通过将小鼠暴露在环境中（记忆检索），记忆将在不同的后调节时间点被重新激活。在这些重新激活的过程中，当小鼠得知周围环境不再与电击相关时，就会出现消退（恐惧消退）。在目标 1 中，我们将评估记忆检索之前 HDACi 的时间进程如何影响 1）行为中恐惧记忆的后续表达以及 2）记忆检索之后 HA 的时间依赖性区域变化。在目标 2 中，我们将在记忆检索试验之前检查 HDACi 输注到不同大脑区域对 (1) 行为增强和消除的影响，以及 (2) 对记忆检索后区域基因表达转录控制的影响。通过结合分子、神经药理学和行为方法，拟议的研究旨在深入了解分子和神经系统，这些系统是减少创伤和焦虑诱发刺激影响的潜在治疗靶点。公共卫生相关性：许多焦虑症，包括创伤后应激障碍，其特征是无法抑制环境刺激引起的强烈精神、情感和身体痛苦。拟议的研究旨在了解大脑区域特定的基因网络如何响应这些引起焦虑的刺激而被激活。通过研究这些分子变化如何映射到与恐惧相关的行为，这项研究将指导未来针对焦虑症设计药物干预措施的研究，通过针对这些基因网络来抑制焦虑诱发刺激的情绪影响。