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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

基本信息

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
项目类别：
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

项目摘要

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