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