Mechanisms of Extinction of Conditioned Fear by Vagus Nerve Stimulation

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减轻症状的药物治疗，但不能针对根本原因。试图用多种药物治疗复杂焦虑症中可能出现的各种症状，增加了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很有前景的替代药物。CBT的目的是康复，而不是治疗症状。认知行为疗法依赖于恐惧消退原理，即暴露在与恐惧相关的线索中，直到学会新的联系。最近的发展表明，辅助治疗可以改善康复。我们的研究表明迷走神经在情感唤起记忆的巩固中起着重要作用。迷走神经是连接外周神经系统和中枢神经系统的桥梁，通过增加大脑的可塑性来应对循环应激激素的增加，从而快速存储有关威胁或情绪激动事件的记忆。迷走神经与交感神经相互作用，对心脏和其他器官产生副交感神经作用。由于这个原因，它被称为“迷走神经刹车”对压力的交感反应。焦虑障碍的特征是迷走神经对压力的反应改变和消除条理性恐惧的能力受损。我们最近发现，在消失训练中刺激迷走神经可以增强大鼠两种形式的条形恐惧的消失。迷走神经刺激（VNS）被联邦食品和药物管理局批准用于治疗癫痫发作和抑郁症，但目前还没有作为辅助治疗。相反，VNS是作为一种起搏器来维持某种大脑状态。提出的研究是基于这样的概念：消退失败会导致焦虑障碍，而刺激迷走神经可以增强消退。如果VNS有望成为治疗焦虑症的新方法，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消失有关。目的1将验证VNS调节经验依赖的可塑性的假设，并研究消退训练、VNS和VNS与消退配对在消退相关神经通路中对可塑性的个体贡献。目的2和3将研究VNS是否影响与自然消失相关的相同的调节和突触系统。这项拟议中的研究将给一个新兴的神经科学中心带来恶名。美国国立卫生研究院的支持将为学生主导的神经科学研究带来稳定，因为这所大学正在通过试验和错误快速发展。四名优秀的本科生都是神经科学专业的学生，他们都立志从事研究和医学工作，平均绩点超过3.7，他们将与两名研究生和两名导师一起提出一个基本问题，即一种潜在的治疗方法是如何起作用的。

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.