A role for orexins in fear learning

食欲素在恐惧学习中的作用

基本信息

批准号：
8411449
负责人：
Robert Milton Sears
金额：
$ 5.13万
依托单位：
NEW YORK 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：
2011-12-16 至 2014-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411449
关键词：
Acute Affect Amygdaloid structure Anxiety Anxiety Disorders Area Arousal Attention Aversive Stimulus Behavior Brain Brain Stem Brain region Cell Nucleus Clinical Conditioned Stimulus Contralateral Cues Data Diagnosis Diagnostic Disease Due Process Emotional Event Freezing Fright Goals Hyperactive behavior Hypothalamic structure Impairment Individual Infusion procedures Lateral Lead Learning Light Measures Mediating Mediator of activation protein Memory Neurons Norepinephrine Panic Disorder Pathway interactions Predisposition Process Propranolol Proton Pump Quality of life Role Sensory Signal Transduction Source Stimulus Stress System Testing Time Training base beta-adrenergic receptor biological adaptation to stress conditioned fear conditioning experience hypocretin locus ceruleus structure long term memory memory retrieval noradrenergic novel orexin 1 receptor promoter receptor receptor expression research study response stress disorder

项目摘要

Anxiety and fear disorders involve alterations of fear processing, due in part to persistent changes in emotional processing circuits in the brain. The overall goal of the current proposal is to elucidate the role of the hypothalamic orexin (hypocretin) system in emotional learning. There is strong evidence that orexins mediate stress and arousal responses to aversive stimuli, which may be required for the formation of negative emotional memories. A well established brain area for the formation, storage and retrieval of these memories, and the first logical target for orexin activity, is the lateral nucleus of the amygdala (LA). However, consistent with low receptor expression in this area, direct pharmacological manipulations of orexin receptor-1 (OrxR1) in LA do not affect aversive learning. Preliminary data suggest that both central and direct locus coeruleus (LC) administration of the orexin receptor-1 (OrxR1) antagonist SB 334867 impairs the acquisition of aversive memories. Indeed, the LC, a major source of brain norepinephrine (NE), receives dense projections from orexin neurons, expresses high levels of OrxR1, and LC neurons are excited by orexins. Based on evidence that locus coeruleus LC and orexin neurons are co-activated in response to aversive stimuli, and that orexins directly excite LC neurons, I hypothesize that orexins can enhance NE release in the LA. Indeed, data from our lab strongly implicate NE signaling through beta-adrenergic receptors (betaARs) in the LA in the learning of fear associations. The current proposal seeks to demonstrate an unexplored interaction between the hypothalamic orexin system and brain regions that are critical for emotional learning. Specifically, I hypothesize that orexins enhance aversive memory formation through positive modulation of the LC during the unconditioned stimulus (US, or stimulus that triggers an innate response) in cued conditioning. First, I will test orexin activity in the LC with an OrxR1 antagonist (SB 334867) pre-training period (acquisition of a memory) and post- training period (consolidation of a memory). Second, to demonstrate a hypothalamus (orexin)->LC(OrxR1)->LA(betaAR) pathway, I will pharmacologically ¿disconnect¿ the circuit using contralateral infusions of SB 334867 in the LC and propranolol in LA. Third, I will use a light-activated channel, Archaerhodopsin-3 (Arch) to inhibit orexin neurons during either the conditioned stimulus (CS, i.e. a tone) or the US to examine when during training orexin modulates LC activity. I hypothesize that orexin neuron inhibition during the US, but not the CS, will facilitate aversive learning. Clinical evidence suggests that people deficient in orexins show impairments in aversive memory formation. Dysregulation of the orexin system may explain susceptibility to fear and anxiety disorders and provide both a diagnostic measure and treatment target for these disorders.

焦虑和恐惧症涉及恐惧处理的改变，部分原因是大脑中情绪处理回路的持续变化。当前提案的总体目标是阐明下丘脑食欲素（下丘脑分泌素）系统在情绪学习中的作用。强有力的证据表明，食欲素介导对厌恶刺激的压力和唤醒反应，这可能是形成负面情绪记忆所必需的，一个完善的大脑区域可以形成、存储和检索这些记忆，食欲素活性的第一个逻辑目标是杏仁核外侧核 (LA)。然而，与该区域的低受体表达一致，直接对 LA 中的食欲素受体 1 (OrxR1) 进行药理学操作不会影响厌恶性学习。初步数据表明，中央和直接蓝斑 (LC) 施用食欲素受体 1 (OrxR1) 拮抗剂 SB 334867 都会损害获得事实上，LC 是大脑去甲肾上腺素 (NE) 的主要来源，它接收来自食欲素神经元的密集投射，表达高水平的 OrxR1，并且 LC 神经元被食欲素兴奋。食欲素对厌恶刺激共同激活，并且食欲素直接刺激 LC 神经元，我认为食欲素可以增强洛杉矶的 NE 释放。事实上，来自我们实验室的数据。强烈暗示 NE 信号通过 LA 中的 β 肾上腺素受体 (betaAR) 参与恐惧关联的学习。目前的提议旨在证明下丘脑食欲素系统和对情绪学习至关重要的大脑区域之间存在未经探索的相互作用，我利用食欲素在无条件刺激（US，或刺激）期间通过 LC 的正向调节来增强厌恶记忆的形成。首先，我将使用 OrxR1 拮抗剂 (SB 334867) 训练前阶段（习得）测试 LC 中的食欲素活性。其次，为了证明下丘脑（食欲素）->LC(OrxR1)->LA(betaAR) 途径，我将在药理学上 ¿断开在 LC 中使用对侧输注 SB 334867，在 LA 中使用普萘洛尔。第三，我将使用光激活通道 Archaerhodopsin-3 (Arch) 在条件刺激（CS，即音调）或条件刺激期间抑制食欲素神经元。在美国检查食欲素何时调节 LC 活性，我发现美国（而不是 CS）期间的食欲素神经元抑制将促进。临床证据表明，食欲素缺乏的人在厌恶性记忆形成方面表现出障碍，食欲素系统的失调可能解释了对恐惧和焦虑症的易感性，并为这些疾病提供了诊断措施和治疗目标。