Enhancing Speech Processing In A Rat Model Of Autism Using Vagus Nerve Stimulation

使用迷走神经刺激增强自闭症大鼠模型的语音处理

• 批准号: 10609721
• 负责人: Crystal T Engineer
• 金额: $ 3.33万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609721
• 关键词: Acetylcholine; Animal Model; Animals; Auditory; Auditory area; Behavior Therapy; Behavioral; Brain-Derived Neurotrophic Factor; Clinical; Communication impairment; Consumption; Data; Development; Discrimination; Exhibits; Future; Goals; Human; Impairment; Implant; Individual; Intervention; Learning; Modeling; Neuromodulator; Neuronal Plasticity; Noise; Norepinephrine; Phase; Process; Rattus; Recovery of Function; Rehabilitation therapy; Role; Saline; Sensory; Series; Speech Discrimination; Speech Perception; Speech Sound; System; Techniques; Testing; Time; Training; Translating; Translations; Valproic Acid; auditory processing; auditory rehabilitation; autism spectrum disorder; awake; base; behavioral outcome; cholinergic; clinical translation; efficacy testing; experience; experimental study; improved; in utero; individuals with autism spectrum disorder; insight; motor rehabilitation; neurophysiology; neuroregulation; noradrenergic; novel; pre-clinical; prenatal; relating to nervous system; response; sound; speech processing; vagus nerve stimulation

One of the major obstacles facing individuals with autism is the inability to communicate effectively. While there are many reasons for this inability, an important component appears to be a serious deficit in the ability to process speech sounds effectively. Expensive, time-consuming behavioral interventions can improve behavioral outcomes, but many individuals undergo these interventions and still experience deficits. The development of adjunctive interventions that can increase the benefit of rehabilitation therapies is essential to improve the lives of individuals with autism spectrum disorders (ASD). We have developed a novel technique to drive robust neuroplasticity and enhance the benefits of rehabilitation. Vagus nerve stimulation (VNS) paired with the presentation of a sound triggers rapid, phasic release of plasticity promoting neuromodulators, which potentiate plasticity in the auditory network. Recent preclinical and clinical findings indicate that VNS paired with sensory or motor rehabilitative therapies can significantly enhance functional recovery compared to rehabilitative therapy alone. This proposal will evaluate whether VNS paired with auditory training can enhance the efficacy of rehabilitation in the context of autism. In utero valproic acid (VPA) exposure is a well-documented cause of autism in humans. Similar to individuals with autism, both speech discrimination ability and auditory cortical responses are impaired in VPA exposed rats. The objective of this proposal is to determine whether VNS paired with auditory training can reverse the neural and behavioral auditory processing deficits observed in VPA exposed rats. In Aim 1, we test the ability of both implanted and non-invasive VNS paired with auditory training to improve discrimination ability after prenatal VPA exposure. VPA exposed rats are significantly impaired at discriminating between speech sounds. We will evaluate discrimination accuracy in VPA or saline exposed rats undergoing VNS paired auditory training. In Aim 2, we evaluate awake behaving neurophysiological responses in auditory cortex to evaluate the VNS-dependent neural plasticity that may underlie improved auditory processing. VPA exposed rats exhibit altered auditory cortex responses compared to control rats. Previous results suggest that VNS pairing may strengthen auditory cortex responses more rapidly and to a greater degree than training alone. In Aim 3, we test the role of two neuromodulatory networks in the VNS-dependent enhancement of plasticity and sound discrimination ability in the context of VPA exposure. We will deplete cholinergic or noradrenergic afferents specifically to the auditory cortex to determine whether acetylcholine or norepinephrine depletion impairs VNS-related improvements in auditory processing. In addition to proof-of- concept evidence for clinical translation, this proposal will provide insight into the ability of plasticity-based therapies to be effective in treating ASD and lay the groundwork for more comprehensive future studies, with the goal of translating these critical first-in-animal preclinical experiments to a clinical therapy that could provide significant, tangible improvements in the lives of individuals with ASD.

自闭症患者面临的主要障碍之一是无法有效沟通。那里 这是造成这种无能的许多原因，重要组成部分似乎是处理能力的严重赤字 语音听起来有效。昂贵，耗时的行为干预可以改善行为 结果，但是许多人接受了这些干预措施，并且仍然遇到赤字。发展的发展 可以增加康复疗法益处的辅助干预措施对于改善生活至关重要 自闭症谱系障碍（ASD）的个体。我们已经开发了一种新颖的技术来推动强大的 神经可塑性并增强康复的益处。迷走神经刺激（VNS）与 声音触发促进神经调节剂的可塑性的快速，阶段性释放的呈现 听觉网络中的可塑性。最近的临床前和临床发现表明，VNS与感觉配对 与康复治疗相比，运动康复疗法可以显着提高功能恢复 独自的。该提案将评估VNS与听觉训练配对是否可以增强 在自闭症的背景下进行康复。在子宫丙酸（VPA）中，暴露是有充分记录的原因 人类的自闭症。与自闭症的人相似，语音歧视能力和听觉皮质 VPA暴露大鼠的反应受损。该建议的目的是确定VN是否配对 通过听觉训练可以扭转VPA中观察到的神经和行为听觉处理缺陷 裸露的大鼠。在AIM 1中，我们测试了植入和非侵入性VN与听觉训练配对的能力 提高产前VPA暴露后的歧视能力。 VPA暴露的大鼠在 区分语音。我们将评估VPA或盐水暴露大鼠的歧视精度 接受VNS配对的听觉培训。在AIM 2中，我们评估了行为神经生理反应的清醒 在听觉皮层中，评估VNS依赖性神经可塑性，这可能是改善听觉的基础 加工。与对照大鼠相比，VPA暴露的大鼠表现出改变的听觉皮层反应。以前的 结果表明，VNS配对可以更快地增强听觉皮层反应 比单独训练。在AIM 3中，我们测试了两个神经调节网络在VNS依赖性中的作用 在VPA暴露的背景下，可塑性和声音歧视能力的增强。我们会耗尽 专门针对听觉皮层的胆碱能或去甲肾上腺素能传入，以确定乙酰胆碱或 去甲肾上腺素的耗竭会损害VNS与听觉处理的改进。除了证明 临床翻译的概念证据，该提案将提供有关基于可塑性的能力的洞察力 疗法有效地治疗ASD并为更全面的未来研究奠定了基础， 将这些关键的第一动物临床前实验转换为可以提供的临床疗法的目标 ASD患者生活的重大，有形的改善。