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。目前许多焦虑症的治疗策略侧重于减轻环境刺激引起精神、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，暴露在引起恐惧的环境刺激中，可以削弱这些刺激引发焦虑反应的能力。消退导致新的抑制性消退记忆的形成，阻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，需要伴随潜在神经网络的变化。最近的研究表明，染色质（DNA包装复合体）通过组蛋白乙酰化（HA）修饰导致记忆形成的分子变化网络（如基因表达）。尽管许多研究表明，用组蛋白去乙酰化酶抑制剂（HDACi）增加HA可以提高学习能力，但令人惊讶的是，我们对HDACi和HA的变化如何调节恐惧记忆的消失和重新激活知之甚少。本提案的主要目标是通过(1)解决神经网络中药理学操作HA如何改变恐惧的再激活和再激活，以及(2)评估HA依赖基因表达的全系统变化如何映射到小鼠恐惧的消失和再激活的行为表达来弥合这一知识差距。为了建立恐惧记忆，老鼠将接受情境恐惧条件反射，在这种条件反射中，暴露在一个新的环境中将伴随着电击。在不同的条件反射后时间点，通过将小鼠暴露在环境中（记忆检索），记忆将被重新激活。在这些再激活事件中，当老鼠知道情境不再与电击相关（恐惧消退）时，灭绝就会发展。在目的1中，我们将评估记忆提取前HDACi的时间过程如何影响1)行为中随后的恐惧记忆表达和2)记忆提取后HA的时间依赖区域变化。在目标2中，我们将研究在记忆检索试验之前将HDACi输注到不同大脑区域对以下方面的影响：(1)行为的增强和消失，以及(2)对记忆检索后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，本研究旨在为减少创伤性和焦虑性刺激影响的潜在治疗靶点提供分子和神经系统的见解。

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.