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: 10050021
• 负责人: Crystal T Engineer
• 金额: $ 38.25万
• 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/10050021
• 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。在那里 造成这种无能的原因有很多，其中一个重要的组成部分似乎是处理能力的严重缺陷 讲话听起来很有效。昂贵、耗时的行为干预可以改善行为 的结果，但许多人接受这些干预措施后仍然会出现缺陷。的发展 可以增加康复治疗益处的辅助干预对于改善生活至关重要 患有自闭症谱系障碍 (ASD) 的个体。我们开发了一种新技术来驱动稳健的 神经可塑性并增强康复的益处。迷走神经刺激（VNS）与 声音的呈现会触发可塑性促进神经调节剂的快速、阶段性释放，从而增强 听觉网络的可塑性。最近的临床前和临床研究结果表明，VNS 与感觉配对 或运动康复治疗与康复治疗相比可以显着增强功能恢复 独自的。该提案将评估 VNS 与听觉训练搭配是否可以增强听觉训练的功效 自闭症背景下的康复。子宫内丙戊酸 (VPA) 暴露是一个有据可查的原因 人类自闭症。与自闭症患者相似，言语辨别能力和听觉皮层 暴露于 VPA 的大鼠的反应受到损害。该提案的目的是确定 VNS 是否配对 通过听觉训练可以逆转 VPA 中观察到的神经和行为听觉处理缺陷 暴露的老鼠。在目标 1 中，我们测试植入式和非侵入式 VNS 与听觉训练相结合的能力 提高产前 VPA 暴露后的辨别能力。暴露于 VPA 的大鼠在 区分语音。我们将评估暴露于 VPA 或盐水的大鼠的辨别准确性 接受 VNS 配对听觉训练。在目标 2 中，我们评估清醒时的神经生理反应 在听觉皮层中评估 VNS 依赖性神经可塑性，这可能是听觉改善的基础 加工。与对照大鼠相比，暴露于 VPA 的大鼠表现出听觉皮层反应的改变。以前的 结果表明，VNS 配对可以更快、更大程度地增强听觉皮层反应 比单独训练。在目标 3 中，我们测试了两个神经调节网络在 VNS 依赖性 在 VPA 暴露的情况下增强可塑性和声音辨别能力。我们将耗尽 胆碱能或去甲肾上腺素能传入神经专门作用于听觉皮层，以确定乙酰胆碱或 去甲肾上腺素耗竭会损害听觉处理中与 VNS 相关的改善。除了证明—— 临床转化的概念证据，该提案将提供对基于可塑性的能力的深入了解 疗法能够有效治疗自闭症谱系障碍，并为未来更全面的研究奠定基础 目标是将这些关键的首次动物临床前实验转化为可以提供 自闭症谱系障碍患者的生活得到显着、切实的改善。