Mechanisms of Extinction of Conditioned Fear by Vagus Nerve Stimulation

迷走神经刺激消除条件性恐惧的机制

• 批准号: 8580886
• 负责人: Christa McIntyre
• 金额: $ 42.99万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580886
• 关键词: AMPA Receptors; Affect; Amygdaloid structure; Animals; Anxiety Disorders; Association Learning; Attenuated; Auditory; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cognitive Therapy; Complex; Coupled; Cues; Data; Depressed mood; Development; Disease; Drug Targeting; Epilepsy; Event; Exposure to; Extinction (Psychology); Failure; Frequencies; Fright; Heart; Hormones; Human; Impairment; Individual; Intervention; K 252a; Lateral; Long-Term Potentiation; Measures; Medicine; Memory; Mental Depression; Mental disorders; Mentors; Motor; N-Methyl-D-Aspartate Receptors; Neural Pathways; Neuraxis; Neurosciences; Neurosciences Research; Neurotrophic Tyrosine Kinase Receptor Type 2; Norepinephrine; Organ; Pacemakers; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phosphorylation; Play; Polypharmacy; Population; Prefrontal Cortex; Prevention; Process; Rattus; Rehabilitation therapy; Reporting; Research; Role; Seizures; Sensory; Serine; Stress; Students; Symptoms; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Time; Tissues; Training; Translating; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Vagus nerve structure; Western Blotting; Work; base; career; conditioned fear; experience; graduate student; improved; intervention effect; noradrenergic; novel; novel strategies; public health relevance; receptor; receptor expression; relating to nervous system; research study; response; undergraduate student; vagus nerve stimulation

DESCRIPTION (provided by applicant): Anxiety disorders are the most common mental illness in the United States. Current treatments include medications that alleviate the symptoms of the disorders but do not target the underlying cause. Attempts to treat the variety of symptoms that can arise in complex anxiety disorders with polypharmacy increase the potential for dangerous interactions. A promising alternative to medication in the treatment of anxiety disorders is Cognitive Behavioral Therapy (CBT). The aim of CBT is to rehabilitate, rather than to treat symptoms. CBT depends on the principle of fear extinction, which involves exposure to fear-associated cues until new associations are learned. Recent developments indicate that rehabilitation can be improved with adjunct therapies. Our research indicates that the vagus nerve plays a role in the consolidation of emotionally arousing memories. The vagus nerve serves as a bridge between the peripheral and central nervous systems, responding to increases in circulating stress hormones by increasing plasticity in the brain to enable rapid storage of memories of threatening or emotionally exciting events. The vagus nerve reciprocates sympathetic activation with parasympathetic effects on the heart and other organs. For this reason it is called the "vagal brake" on the sympathetic response to stress. Anxiety disorders are characterized by altered vagal responses to stress and impaired ability to extinguish conditioned fear. We recently discovered that stimulation of the vagus nerve during extinction training enhanced extinction of two forms of conditioned fear in rats. Vagus nerve stimulation (VNS) is approved by the Federal Food and Drug Administration for treatment of epileptic seizures and depression, but it is not currently administered as adjunct therapy. Instead, VNS is administered as a pacemaker to maintain a certain brain state. The proposed research is based on the concept that extinction failure leads to anxiety disorders and stimulation of the vagus nerve can enhance extinction. If VNS holds promise as a novel approach to the treatment of anxiety disorders, the mechanism/s of action should be better understood. The projection from the infralimbic cortex to the amygdala is implicated in extinction. Aim 1 will test the hypothesis that VNS modulates experience-dependent plasticity and the individual contributions of extinction training, VNS, and VNS paired with extinction on plasticity in an extinction-related neural pathway will be investigated. Aims 2 and 3 will examine whether VNS affects the same modulatory and synaptic systems that are involved in natural extinction. The proposed research will bring notoriety to a burgeoning center for neuroscience. NIH support will bring stability to student-led neuroscience research at a time when the university is rapidly growing by trial and error. Four exceptional undergraduate students, all neuroscience majors aspiring to careers in research and medicine and with GPAs over 3.7, will join two graduate students and two mentors to ask the basic question of how a potential therapy works.

描述（由申请人提供）：焦虑症是美国最常见的精神疾病。目前的治疗方法包括缓解疾病症状但不针对根本原因的药物。尝试用多种药物治疗复杂焦虑症可能出现的各种症状会增加危险相互作用的可能性。认知行为疗法（CBT）是治疗焦虑症的一种有前途的药物替代疗法。 CBT 的目的是康复，而不是治疗症状。 CBT 依赖于恐惧消退的原理，即接触与恐惧相关的线索，直到习得新的关联。最近的发展表明，辅助疗法可以改善康复。 我们的研究表明迷走神经在巩固情绪唤起的记忆中发挥着作用。迷走神经是周围神经系统和中枢神经系统之间的桥梁，通过增加大脑的可塑性来响应循环应激激素的增加，从而能够快速存储威胁或情绪激动事件的记忆。迷走神经交互激活交感神经，并对心脏和其他器官产生副交感神经作用。因此，它被称为交感神经对压力反应的“迷走神经制动”。焦虑症的特点是迷走神经对压力的反应改变以及消除条件性恐惧的能力受损。我们最近发现，在消退训练过程中刺激迷走神经可以增强大鼠两种形式的条件性恐惧的消退。迷走神经刺激 (VNS) 已获得联邦食品和药物管理局批准用于治疗癫痫发作和抑郁症，但目前不作为辅助治疗。相反，迷走神经刺激作为起搏器来维持某种大脑状态。 拟议的研究基于这样的概念：消退失败会导致焦虑症，而刺激迷走神经可以增强消退。如果 VNS 有希望成为治疗焦虑症的一种新方法，那么其作用机制应该得到更好的理解。从边缘下皮层到杏仁核的投射与灭绝有关。目标 1 将检验 VNS 调节经验依赖性可塑性的假设，并将研究消退训练、VNS 以及 VNS 与消退配对对消退相关神经通路中可塑性的个体贡献。目标 2 和 3 将检查 VNS 是否影响参与自然灭绝的相同调节和突触系统。拟议的研究将为新兴的神经科学中心带来恶名。 NIH 的支持将为学生主导的神经科学研究带来稳定性，而此时该大学正在通过反复试验而迅速发展。四名优秀的本科生，所有神经科学专业的学生，​​都渴望从事研究和医学事业，并且 GPA 超过 3.7，他们将与两名研究生和两名导师一起提出潜在疗法如何发挥作用的基本问题。

项目成果

Corticosterone-induced enhancement of memory and synaptic Arc protein in the medial prefrontal cortex.

• DOI: 10.1016/j.nlm.2014.02.007
• 发表时间: 2014-07
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: McReynolds JR;Holloway-Erickson CM;Parmar TU;McIntyre CK
• 通讯作者: McIntyre CK

Emotional modulation of synapses, circuits and memory.

突触、电路和记忆的情绪调节。

• DOI: 10.3389/fnbeh.2015.00035
• 发表时间: 2015
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Ploski,JonathanE;McIntyre,ChristaK
• 通讯作者: McIntyre,ChristaK

Peripheral effects of vagus nerve stimulation on anxiety and extinction of conditioned fear in rats.

迷走神经刺激对大鼠焦虑和条件性恐惧消除的外周影响。

• DOI: 10.1101/lm.048447.118
• 发表时间: 2019
• 期刊: Learning & memory (Cold Spring Harbor, N.Y.)
• 作者: Noble,LindseyJ;Chuah,Ashleigh;Callahan,KathleenK;Souza,RimenezR;McIntyre,ChristaK
• 通讯作者: McIntyre,ChristaK