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: 10616604
• 负责人: Christa McIntyre
• 金额: $ 53.54万
• 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/10616604
• 关键词: Acceleration; Affect; Amygdaloid structure; Anatomy; Animals; Anxiety; Anxiety Disorders; Area; Arousal; Axon; Behavioral; Brain; Bypass; Cervical; Coupled; Cues; Data; Development; Disease; Dropout; Emotional; Epinephrine; Exhibits; Experimental Designs; Exposure to; Extinction; Fright; Goals; Hippocampus; Human; Impairment; Individual; Infusion procedures; 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; Rat Transgene; Rattus; Research; Role; Signal Transduction; Site; Stimulus; Synapses; Synaptic plasticity; Testing; Thinking; Training; Trauma; Tyrosine 3-Monooxygenase; Vagus nerve structure; Work; behavior test; behavioral extinction; conditioned fear; conditioning; experience; fear memory; fighting; improved; innovation; insight; learning extinction; locus ceruleus structure; memory acquisition; memory consolidation; neural; neuromechanism; neuroregulation; noradrenergic; optogenetics; patient population; pre-clinical; prevent; 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.

项目概要 情感创伤经历会导致持久且侵入性的适应不良记忆。目标 基于暴露的疗法的目的是通过重复的、非强化的暴露来消除条件性恐惧 创伤事件的提醒。条件性恐惧的消除取​​决于新的恐惧的巩固 接触提醒时产生的记忆。在某些患者中观察到的消退记忆受损 人群，可能会干扰基于暴露的疗法的进展，以及避免思想和想法的动力 提醒人们创伤可能会破坏依从性并增加辍学率。开发有效的 辅助治疗将理想地提高治疗的耐受性和/或改善巩固和治疗 维持灭绝记忆。 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）可增强基于恐惧的记忆的消除。在压力条件下，迷走神经 对肾上腺素的升高做出反应并向大脑发出信号以促进新记忆的存储 作为副交感神经系统的一部分，它会减慢交感神经的“战斗或逃跑”反应。我们建议 在暴露于条件信号期间刺激左颈迷走神经，向大脑发出信号以存储新的信号 记忆就像肾上腺素或情绪唤醒一样，但绕过了外周交感神经反应。 为了支持这一假设，我们发现 VNS 加速了灭绝，逆转了灭绝损伤， 促进灭绝的普遍化，并防止大鼠条件性恐惧的恢复。 VNS 被认为通过增加整个大脑神经调节剂的活性来发挥作用，产生突触 有利于塑性的状态。特别是，蓝斑 (LC) 被认为在 VNS 中发挥着关键作用 通过直接向灭绝网络的多个区域提供去甲肾上腺素能输入来发挥功效，包括 前额皮质（PFC）、基底外侧杏仁核（BLA）和海马体（HIP）。在此，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，证明 VNS 可能是一种有效的辅助手段 基于暴露的疗法。为了阐明 VNS 促进其作用的机制，我们建议 光遗传学操纵 LC，并在调节过程中同时记录 PFC、BLA 和 HIP， 灭绝和灭绝后行为测试。 通过增加我们对 VNS 增强条件性恐惧消除机制的理解， 这些研究将支持患者的治疗开发，并提供新的基本见解 LC信号对消退相关可塑性的神经调节机制。