Behavioral and Molecular Analysis of Chromatin Modifications in Memory Retrieval

描述（由申请人提供）：每年至少有18%的美国人患有焦虑症。目前对许多焦虑症的治疗策略集中在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。消退导致形成新的抑制性消退记忆，阻止刺激重新激活这种强大的情感反应，因此是一个主动过程，需要伴随底层神经网络的变化。最近的研究表明，通过组蛋白乙酰化（HA）修饰染色质（DNA包装复合物）导致分子变化网络（例如，基因表达）的潜在记忆形成。虽然许多研究表明，增加HA与组蛋白去乙酰化酶抑制剂（HDACi）增强学习，我们知道如何HDACi和HA的变化调节恐惧记忆消退和再激活令人惊讶的是少。 该提案的主要目标是通过以下方式弥合这一知识差距：（1）解决神经网络内的人工操纵HA如何改变恐惧再激活和消退，以及（2）评估HA依赖性基因表达的系统范围变化如何映射到小鼠恐惧消退和再激活的行为表达中。为了建立恐惧记忆，小鼠将接受情境恐惧条件反射，其中暴露于新的情境将与电击配对。通过将小鼠暴露于环境（记忆提取），记忆将在不同的后调节时间点重新激活。在这些再激活事件中，随着小鼠了解到环境不再与休克相关（恐惧消退），消退将发展。在目标1中，我们将评估在记忆恢复之前HDACi的时间过程如何影响1）行为中恐惧记忆的后续表达和2）记忆恢复之后HA的时间依赖性区域变化。在目标2中，我们将检查在记忆检索试验之前HDACi输注到不同脑区域对（1）行为的增强和消退的影响，以及（2）记忆检索后对区域基因表达的转录控制的影响。 通过结合分子，神经药理学和行为学方法，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导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，其特征是无法抑制由环境刺激引起的强大的精神、情感和身体痛苦。这项拟议中的研究旨在了解大脑区域特定的基因网络是如何被激活以响应这些焦虑诱导刺激的。通过研究这些分子变化如何映射到与恐惧相关的行为中，这项研究将指导未来的研究，为焦虑症设计药物干预措施，通过靶向这些基因网络来抑制焦虑诱导刺激的情绪影响。

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.