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缓解疾病症状的药物，但不针对根本原因。试图用多种药物治疗复杂焦虑症可能出现的各种症状，增加了危险相互作用的可能性。一个有前途的替代药物治疗焦虑症是认知行为疗法（CBT）。CBT的目的是康复，而不是治疗症状。CBT依赖于恐惧消退的原则，这涉及暴露于与恐惧相关的线索，直到学习到新的关联。最近的发展表明，康复可以改善辅助治疗。 我们的研究表明，迷走神经在巩固情感唤起记忆方面发挥着作用。迷走神经作为外周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。迷走神经与交感神经激活相互作用，对心脏和其他器官产生副交感神经效应。由于这个原因，它被称为“迷走神经制动”的交感神经反应的压力。焦虑症的特征是对压力的迷走神经反应改变，消除条件性恐惧的能力受损。我们最近发现，在消退训练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，但目前尚未作为辅助治疗。相反，VNS作为起搏器来维持一定的大脑状态。 这项研究是基于这样一个概念，即灭绝失败会导致焦虑症，刺激迷走神经可以增强灭绝。如果迷走神经刺激有望成为治疗焦虑症的一种新方法，那么应该更好地理解其作用机制。从边缘下皮层到杏仁核的投射与灭绝有关。目的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和VNS与消退配对对消退相关神经通路中可塑性的个体贡献。目的2和3将研究VNS是否影响与自然灭绝有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。NIH的支持将为学生主导的神经科学研究带来稳定性，因为大学正在通过试验和错误快速发展。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，GPA超过3.7，将与两名研究生和两名导师一起询问潜在疗法如何工作的基本问题。

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.