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

自闭症患者面临的主要障碍之一是无法有效沟通。在那里的时候 造成这种能力的原因有很多，一个重要的组成部分似乎是处理能力的严重缺陷 语音听起来很有效。昂贵、耗时的行为干预可以改善行为 结果，但许多人接受了这些干预措施，但仍有赤字。的发展。 能够增加康复治疗收益的辅助干预对于改善生活是必不可少的 患有自闭症谱系障碍(ASD)的人。我们已经开发出一种新的技术来驱动健壮 神经可塑性和增强康复的好处。迷走神经刺激(VNS)与 声音的呈现会触发促进可塑性的神经调节剂的快速、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 或者与康复治疗相比，运动康复疗法可以显著促进功能恢复。 独自一人。这项建议将评估VNS与听觉训练相结合是否可以增强 自闭症背景下的康复。在子宫内接触丙戊酸(VPA)是一个有充分证据的原因 人类的自闭症。与自闭症患者相似，无论是言语辨别能力还是听觉皮质 暴露于VPA的大鼠的反应受到损害。该提案的目标是确定VNS是否配对 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，我们测试了植入的和非侵入性的VNS结合听觉训练的能力 目的：提高产前VPA暴露后的辨别能力。暴露于VPA的大鼠在 辨别语音。我们将评估VPA或生理盐水暴露大鼠的辨别准确性 接受VNS配对听觉训练。在目标2中，我们评估清醒状态下的神经生理反应 以评估VNS依赖的神经可塑性，这可能是改善听力的基础 正在处理。与对照大鼠相比，暴露于VPA的大鼠表现出听觉皮质反应的改变。上一首 结果表明，VNS配对可以更快、更大程度地增强听觉皮质的反应 而不是一个人训练。在目标3中，我们测试了两个神经调节网络在VNS依赖中的作用 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听觉皮质，以确定乙酰胆碱或去甲肾上腺素 去甲肾上腺素的耗竭损害了VNS相关听觉处理的改善。除了证明- 为临床翻译提供概念证据，这一建议将为洞察可塑性基础能力提供依据 治疗ASD的有效方法，并为未来更全面的研究奠定基础， 目标是将这些关键的首个动物临床前实验转化为一种临床疗法，可以提供 对自闭症患者的生活有显著的、切实的改善。

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.