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

项目摘要 精神创伤性经历会导致适应不良的记忆，这些记忆是持久的和侵入性的。目标 基于确定性的治疗方法是通过反复的、未经强化的暴露来消除条件性恐惧， 创伤事件的回忆有条件的恐惧的消失取决于新的恐惧的巩固。 在暴露于提醒物时产生的记忆。在某些患者中观察到的消退回忆障碍 人群中，可以干扰以自我为基础的治疗的进展，以及避免思想和 创伤的提醒可能会破坏依从性并增加辍学率。发展一个有效的 连续治疗将理想地改善治疗的耐受性和/或改善巩固， 灭绝记忆的维护 我们最近在大鼠中证明，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失。在压力条件下，迷走神经 对肾上腺素的升高作出反应，并向大脑发出信号，以促进新记忆的储存， 作为副交感神经系统的一部分，它减缓了交感神经的“战斗或逃跑”反应。我们建议 在暴露于条件线索期间刺激左颈迷走神经向大脑发出信号以存储新的信息。 就像肾上腺素或情绪唤起一样，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，逆转了灭绝障碍， 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质的活性来起作用的， 有利于可塑性的状态。特别是，蓝斑（LC）被认为在VNS中起关键作用 通过直接向消光网络的多个区域提供去甲肾上腺素能输入，包括 前额叶皮层（PFC）、基底外侧杏仁核（BLA）和海马体（HIP）。在这里，我们建议 行为实验，旨在评估VNS是否产生更持久和更广泛的灭绝 记忆，这将提供重要的临床前证据，VNS可能是一种有效的辅助手段， 基于安全的治疗。为了阐明VNS促进其作用的机制，我们建议 光遗传学操纵LC，并在调节期间同时记录PFC、BLA和HIP， 灭绝和灭绝后的行为测试。 通过增加我们对VNS增强条件性恐惧消退的机制的理解， 这些研究将支持患者的治疗开发，并提供新的基本见解， LC信号对脑电可塑性的调节机制。

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.