A role for orexins in fear learning

食欲素在恐惧学习中的作用

• 批准号: 8585887
• 负责人: Robert Milton Sears
• 金额: $ 5.51万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 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/8585887
• 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

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.

焦虑和恐惧障碍涉及恐惧处理的改变，部分原因是大脑情绪加工电路的持续变化。当前提案的总体目标是阐明下丘脑OREXIN（低螺旋蛋白）系统在情绪学习中的作用。有强有力的证据表明，奥列赛素对厌恶刺激的中值压力和唤醒反应，这可能是形成负面情绪记忆所必需的。这些记忆的形成，储存和检索以及奥毛蛋白活性的第一个逻辑靶标的大脑面积是杏仁核（LA）的侧向核心。然而，与该区域中低受体表达一致，在LA中，Orexin受体1（ORXR1）的直接药物操纵不会影响厌恶性学习。初步数据表明，中央和直接基因座（LC）给予Orexin受体-1（ORXR1）拮抗剂SB 334867损害厌恶记忆的获取。实际上，LC是脑去甲肾上腺素（NE）的主要来源，从OREXIN神经元获得密集的投影，表达高水平的ORXR1，而LC神经元受到Orexins的激发。基于证据表明coeruleus lc和Orexin神经元响应厌恶刺激而共激活，而Orexin直接激发了LC神经元，我假设Orexins可以增强LA中的NE释放。实际上，我们实验室的数据强烈暗示了通过LA中的β-肾上腺素能受体（β）在学习恐惧关联中的信号传导。 当前的提案旨在证明下丘脑的奥甲蛋白系统与大脑区域之间的意外相互作用，这对于情绪学习至关重要。具体而言，我假设Orexins通过在暗示条件中的无条件刺激（US或触发先天反应的刺激（US或刺激）过程中，通过对LC的积极调节来增强厌恶记忆的形成。首先，我将使用ORXR1拮抗剂（SB 334867）在LC中测试Orexin Active（SB 334867）训练期（记忆的获取）和训练后（记忆的整合）。其次，为了证明下丘脑（orexin） - > lc（orxr1） - > la（betaar）途径，我将使用LC和propranolol在LA中使用SB 334867的对比度输注来断开连接。第三，我将使用光激活的通道，古hopopsin-3（ARCH）来抑制条件刺激（CS，即音调）或美国在训练Orexin调制期间LC活性期间检查OREXIN神经元。我假设在美国而不是CS期间的Orexin神经元抑制作用将有助于厌恶学习。临床证据表明，在甲状腺素中，人们确定的厌恶记忆形成障碍。 Orexin系统的失调可能解释了对恐惧和焦虑症的敏感性，并为这些疾病提供了诊断性测量和治疗靶标。