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(由申请者提供)：学习重组大脑活动，以编码对情感事件的长期记忆。这些记忆通过引导诸如追求食物和避免威胁等适应性行为来提高存活率。然而，在6.8%的美国人中，高达14%-16%的美国军人经历创伤会导致严重的反复出现的焦虑和恐惧，创伤事件的提醒加剧了这种焦虑和恐惧。这种综合症被称为创伤后应激障碍(PTSD)，与恐慌和恐惧症等与恐惧相关的障碍有共同之处，其特征是持续不断地重新体验创伤情绪。目前对创伤后应激障碍的治疗可以缓解一些症状，但对一些人并不起作用，而且随着时间的推移，由于复发，往往会变得无效。在实验室里，情绪反应的获得和衰减可以通过巴甫洛夫式的恐惧、条件反射和消退来模拟。这些研究表明，阻碍创伤后应激障碍恢复的一个因素可能是暴露在与压力相关的神经递质中。这项研究的目标是确定哪些细胞和大脑通路介导神经递质去甲肾上腺素的不利影响。在初步实验中，我们确定去甲肾上腺素信号通过A1肾上腺素受体亚型激活抑制性神经元，并增加它们在杏仁核的传递，杏仁核是恐惧条件反射的关键大脑区域，也是创伤后应激障碍异常活动的部位。 此外，我们还表明，这些受体促进形成抵抗消退的恐惧记忆，这是一个抑制恐惧的过程，类似于基于暴露的情绪疗法。这项提议的目的是定义当被去甲肾上腺素激活时，阻碍灭绝的特定电路机制。我们的具体目标是：1.确定特定的抑制细胞类型在去甲肾上腺素依赖的回路修饰中的作用；2.测试这些抑制神经元对行为灵活性的影响；3.建立灭绝成功和失败的回路决定因素。我们将依靠转基因小鼠、膜片钳电生理学、光遗传学和化学遗传学来实现这些目标。这些实验的结果将确定细胞类型以及突触路径，改进的情绪减弱疗法可以针对这些路径。