Vagus nerve stimulation targets fear pathways to enhance extinction of conditioned fear

迷走神经刺激针对恐惧通路以增强条件性恐惧的消除

• 批准号: 10467846
• 负责人: Christa McIntyre
• 金额: $ 55.56万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467846
• 关键词: Affect; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Arousal; Axon; Behavioral; Brain; Bypass; Cervical; Coupled; Cues; Data; Development; Disease; Dropout; Emotional; Epinephrine; Exhibits; Exposure to; Extinction (Psychology); Fright; Goals; Gold; Hippocampus (Brain); Human; Impairment; Individual; Infusion procedures; Lead; Learning; Left; Maintenance; Medial; Mediating; Memory; Microdialysis; Neuromodulator; Neurons; Norepinephrine; Parasympathetic Nervous System; Pathway interactions; Patients; Pattern; Peripheral; Persons; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Publishing; Rattus; Research; Role; Signal Transduction; Stimulus; Synapses; Synaptic plasticity; Testing; Thinking; Training; Transgenic Organisms; Trauma; Tyrosine 3-Monooxygenase; Vagus nerve structure; Work; base; behavior test; conditioned fear; conditioning; design; experience; experimental study; fear memory; fighting; improved; innovation; insight; learning extinction; locus ceruleus structure; memory consolidation; neuromechanism; neuroregulation; noradrenergic; optogenetics; patient population; pre-clinical; prevent; relating to nervous system; response; standard of care; success; therapeutic development; therapy development; traumatic event; vagus nerve stimulation

PROJECT SUMMARY Emotionally traumatic experiences can lead to maladaptive memories that are enduring and intrusive. The goal of exposure-based therapies is to extinguish conditioned fears through repeated, unreinforced exposures to reminders of traumatic events. The extinction of conditioned fear depends upon the consolidation of new memories made during exposure to reminders. An impairment in extinction recall, observed in certain patient populations, can interfere with progress in exposure-based therapies, and the drive to avoid thoughts and reminders of the trauma can undermine compliance and increase dropout rate. Development of an effective adjunctive therapy would ideally improve the tolerability of therapy and/or improve the consolidation and maintenance of the extinction memory. We have recently demonstrated in rats that, compared to exposure alone, exposure paired with vagus nerve stimulation (VNS) enhances the extinction of fear-based memories. Under stressful conditions, the vagus nerve responds to elevations in epinephrine and signals the brain to facilitate the storage of new memories while, as part of the parasympathetic nervous system, it slows the sympathetic “fight-or-flight” response. We propose that stimulation of the left cervical vagus nerve during exposure to conditioned cues signals the brain to store new memories just as epinephrine or emotional arousal would do but bypasses the peripheral sympathetic response. In support of this hypothesis, we have found that VNS accelerates extinction, reverses extinction impairments, promotes generalization of extinction, and prevents reinstatement of conditioned fear in rats. VNS is thought to work by increasing the activity of neuromodulators throughout the brain, producing a synaptic state that is conducive to plasticity. In particular, the locus coruleus (LC) is thought to play a critical role in VNS efficacy by supplying noradrenergic input directly to multiple regions of the extinction network, including the prefrontal cortex (PFC), the basolateral amygdala (BLA), and the hippocampus (HIP). Here, we propose behavioral experiments designed to evaluate whether VNS produces more persistent and generalized extinction memories, which would provide important preclinical evidence that VNS could be an effective adjunct to exposure-based therapies. To elucidate the mechanisms by which VNS promotes its effects, we propose to optogenetically manipulate the LC, and to simultaneously record from PFC, BLA, and HIP during conditioning, extinction, and post-extinction behavioral testing. By increasing our understanding of the mechanisms by which VNS enhances extinction of conditioned fear, these studies will support treatment development for patients, and provide new fundamental insights into the neuromodulatory mechanisms of LC signaling on extinction-related plasticity.

项目总结 情感创伤的经历可能会导致持久的、侵入性的不适应记忆。目标是 以暴露为基础的疗法的核心是通过反复、无强化地暴露于 让人想起创伤性事件。条件性恐惧的消失有赖于新的 在接触提醒的过程中产生的记忆。在某些患者中观察到的消亡记忆障碍 人群，会干扰以暴露为基础的治疗的进展，以及避免思想和 对创伤的提醒可能会破坏遵从性并增加辍学率。开发一种有效的 辅助治疗将理想地提高治疗的耐受性和/或改善巩固和 维持消亡记忆。 我们最近在大鼠身上证明，与单独暴露相比，暴露与迷走神经配对 刺激(VNS)增强了基于恐惧的记忆的消退。在应激条件下，迷走神经 对肾上腺素的升高作出反应，并向大脑发出信号，以促进新记忆的存储，如 作为副交感神经系统的一部分，它减缓了交感神经的“非战即逃”反应。我们建议 刺激左侧颈迷走神经在暴露于条件线索的过程中向大脑发出信号以存储新的 记忆就像肾上腺素或情绪唤醒一样，只是绕过了外周交感反应。 为了支持这一假设，我们发现VNS加速了物种灭绝，逆转了物种灭绝损伤， 促进灭绝的泛化，并防止大鼠条件性恐惧的恢复。 VNS被认为是通过增加整个大脑中神经调节器的活性，产生突触来发挥作用的 有利于可塑性的状态。特别是，冠状核(LC)被认为在VNS中起关键作用。 直接向灭绝网络的多个区域提供去甲肾上腺素能输入的疗效，包括 前额叶皮质(PFC)、基底外侧杏仁核(BLA)和海马体(HIP)。在这里，我们建议 旨在评估VNS是否会产生更持久和更广泛的灭绝的行为实验 记忆，这将提供重要的临床前证据，表明VNS可能是一种有效的辅助 基于暴露的疗法。为了阐明VNS促进其作用的机制，我们建议 光遗传学操作LC，并在条件作用期间同时记录PFC、BLA和HIP， 灭绝，以及灭绝后的行为测试。 通过增加我们对VNS增强条件性恐惧消退机制的理解， 这些研究将支持患者的治疗开发，并提供新的基本见解 LC信号对消亡相关可塑性的神经调制机制。