Noradrenergic circuit mechanisms of persistent fear

持续恐惧的去甲肾上腺素能回路机制

• 批准号: 8800033
• 负责人: Roger L Clem
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800033
• 关键词: Adaptive Behaviors; Address; Adrenergic Agents; Adverse effects; Affect; American; Amygdaloid structure; Animals; Anxiety; Area; Attenuated; Auditory; Behavior; Behavioral; Brain; Brain region; Cells; Coupled; Cues; Data; Designer Drugs; Disease; Disease remission; Electrophysiology (science); Elements; Emotional; Emotions; Event; Exposure to; Extinction (Psychology); Failure; Food; Fright; GTP-Binding Proteins; Goals; Hippocampus (Brain); Impairment; In Vitro; Individual; Interneurons; Laboratories; Learning; Medial; Mediating; Memory; Metabolic; Military Personnel; Modeling; Modification; Mus; Nature; Neuromodulator; Neuronal Plasticity; Neurotransmitters; Norepinephrine; Outcome; Panic; Parvalbumins; Pathway interactions; Pharmacology; Phobias; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychological reinforcement; RNA; Receptor Cell; Receptor Signaling; Recovery; Recurrence; Relapse; Resistance; Retrieval; Role; Services; Signal Transduction; Site; Somatostatin; Staging; Stimulus; Stress; Symptoms; Synapses; Syndrome; System; Testing; Time; Training; Transgenic Mice; Trauma; Work; adrenergic; alpha-1 adrenergic receptors; attenuation; base; brain pathway; cell type; conditioned fear; emotional experience; experience; fear memory; flexibility; gamma-Aminobutyric Acid; improved; in vivo; inhibitory neuron; member; neuronal circuitry; noradrenergic; novel; optogenetics; patch clamp; preclinical study; public health relevance; receptor; research study; response; success; transmission process; traumatic event

DESCRIPTION (provided by applicant): Learning reorganizes brain activity to encode long-lasting memories of emotional events. These memories enhance survival by guiding adaptive behaviors like pursuit of food and avoidance of threats. However, in 6.8% of Americans, and as high as 14-16% of U.S. military service members, the experience of trauma leads to severe and recurrent anxiety and fear, exacerbated by reminders of the traumatic event. This syndrome, known as post-traumatic stress disorder (PTSD), shares commonalities with fear-related disorders like panic and phobia, and is characterized by persistent re-experiencing of traumatic emotion. Current treatments for PTSD confer some remission of symptoms, but do not work in some individuals, and frequently become ineffective over time due to relapse. Acquisition and attenuation of emotional responses can be modeled in the laboratory by Pavlovian fear conditioning and extinction. These studies have suggested that one factor impeding recovery from PTSD may be exposure to stress-related neurotransmitters. The goal of this study is to define which cells and brain pathways mediate adverse effects of the neurotransmitter noradrenaline. In preliminary experiments, we determined that noradrenaline signals through the a1 adrenoreceptor subtype to activate inhibitory neurons and increase their transmission in the amygdala, a critical brain region in fear conditioning and a site of abnormal activity in PTSD. Furthermore, we show that these receptors promote formation of fear memories that are resistant to extinction, a process for inhibiting fear that is analogous to exposure-based emotional therapies. The objective of this proposal is to define the specific circuit mechanisms that, when activated by noradrenaline, impede extinction. Our specific aims are 1. To establish the role of specific inhibitory cell types in noradrenaline-dependent circuit modifications, 2. To test the impact of these inhibitory neurons on behavioral flexibility, and 3. To establish circuit determinants of extinction success and failure. We will rely on transgenic mice, patch-clamp electrophysiology, optogenetics and chemicogenetics to accomplish these goals. The results of these experiments will define cell types as well as synaptic pathways at which improved therapies for attenuating emotion can be directed.

描述（由申请人提供）：学习重组大脑活动，以编码情感事件的长期记忆。这些记忆通过指导自适应行为（例如追求食物和避免威胁）来增强生存。但是，在6.8％的美国人中，高达14-16％的美国兵役成员，创伤经历导致了严重和反复的焦虑和恐惧，这使人们想起了创伤事件。该综合征被称为创伤后应激障碍（PTSD），具有与恐惧和恐惧症等恐惧相关疾病的共同点，其特征是对创伤性情绪的持续重新体验。 PTSD的当前治疗方法赋予了一些症状缓解，但在某些人中不起作用，并且由于复发而经常随着时间的流逝而无效。可以通过帕夫洛维亚的恐惧调节和灭绝在实验室中对情感反应的获取和衰减进行建模。这些研究表明，阻碍PTSD恢复的一​​个因素可能是暴露于与压力相关的神经递质中。这项研究的目的是定义哪些细胞和脑途径介导神经递质去甲肾上腺素的不良反应。在初步实验中，我们确定通过A1肾上腺受体亚型的去甲肾上腺素信号激活抑制性神经元并增加其在杏仁核中的传播，杏仁核是恐惧调节中的关键大脑区域，并且是PTSD中异常活性的部位。 此外，我们表明这些受体促进了抗灭绝的恐惧记忆的形成，这是抑制类似于基于暴露的情绪疗法的恐惧的过程。该提案的目的是定义特定的电路机制，这些电路机制被去甲肾上腺素激活时会阻碍灭绝。我们的具体目的是1。确定特定抑制性细胞类型在去甲肾上腺素依赖性电路修饰中的作用，2。测试这些抑制性神经元对行为灵活性的影响，以及3。建立灭绝成功和失败的电路决定因素。我们将依靠转基因小鼠，斑块钳电生理学，光遗传学和化学遗传学来实现这些目标。这些实验的结果将定义细胞类型以及突触途径，在这些途径中，可以将改进的疗法可降低情绪。