Corticostriatal Contributions to Auditory Perceptual Hypersensitivity

项目总结/摘要 在整个感觉系统中，外周输入的剥夺与神经系统的代偿性增加有关。 感觉皮层的兴奋性。通常情况下，这种补偿过程超过了标准， 沿着对感觉刺激的知觉超敏反应。这样的观察有着悠久的历史 在听觉系统中：噪声引起的耳蜗损伤与反常的皮质 多动和知觉异常，如听觉过敏，一种以听觉障碍为特征的听觉障碍， 增加感知响度到中等强度的声音。尽管人们相信大脑皮层过度活跃 是感知超敏反应背后的驱动力，但确切的联系尚不清楚。这种指导性培训 该项目将结合联合收割机慢性行为，双光子成像和小鼠光遗传学技术， 了解以下行为超敏表型出现的神经变化 高频噪音引起的听力损失根据目标1进行的研究将制定一个两种备选方案， 选择任务，评估头部固定小鼠的响度感知。这种行为提供了两个主要的 进展：i）直接评估噪声暴露后的感知超敏反应，以及ii） 行为正常的小鼠的慢性成像。目标2中的研究将使用听觉的慢性双光子钙成像 皮质纹状体神经元，一种与神经行为直接相关的确定的细胞类型。将进行成像 在被动和任务参与的条件下，都可以充分表征频率和强度 在整个tonotopic地图的反应变化，并能够直接比较神经活动的变化， 知觉决策目的3验证诱发皮质纹状体听觉兴奋性过度的假说 在具有健康耳蜗的未暴露对照小鼠中， 将中等强度的声音归类为大声。皮质纹状体神经元会被移入移出 使用稳定的阶跃函数视蛋白暂时诱导稳定和可逆的 在正常的行为小鼠中过度兴奋。总而言之，该项目将克服以前的技术限制 为了更全面地了解听觉感知的神经回路病理学， 超敏反应除了外周损伤外，感觉超敏反应还与其他疾病有关， 衰老和神经发育障碍，包括自闭症。因此，从这个项目到神经的洞察力， 多动和行为超敏性的特征将被证明对听力损伤有广泛的价值， 其他感觉障碍和相关的神经系统疾病。

Project Summary/Abstract Across sensory systems, a deprivation of peripheral input is associated with a compensatory increase in neural excitability at the level of sensory cortex. Commonly, this compensatory process overshoots the mark, resulting in hyperactivity along with perceptual hypersensitivity to sensory stimuli. Such observations have a long history in the auditory system: noise-induced damage to the cochlea is associated with a paradoxical cortical hyperactivity and perceptual abnormalities such as hyperacusis, an auditory disorder characterized by an increase in perceived loudness to moderately intense sounds. Although it is believed that cortical hyperactivity is a driving force behind perceptual hypersensitivity, a definitive link is yet unclear. This mentored training project will combine chronic behavioral, two-photon imaging, and optogenetics techniques in mice to understand the neural changes underlying the emergence of a behavioral hypersensitivity phenotype following a high frequency noise-induced hearing loss. Studies pursuant to Aim 1 will develop a two-alternative forced choice task that assesses loudness perception in head-fixed mice. Such a behavior provides two major advances: i) direct evaluation of perceptual hypersensitivity after noise exposure, and ii) the ability to do chronic imaging in behaving mice. Studies in Aim 2 will use chronic two-photon calcium imaging of auditory corticostriatal neurons, a defined cell type directly relevant to auditory-guided behavior. Imaging will take place in both passive and task-engaged conditions both to allow full characterization of frequency and intensity response changes across the tonotopic map and to enable direct comparison of neural activity changes with perceptual decision-making. Aim 3 will test the hypothesis that inducing auditory corticostriatal hyperexcitability in unexposed control mice with healthy cochleae is sufficient to increase the probability of perceptually categorizing moderately intense sounds as loud. Corticostriatal neurons will be shifted in and out of hyperactive states using stabilized step function opsins to temporarily induce stable and reversible planes of hyperexcitability in normal, behaving mice. Altogether, this project will overcome previous technical limitations to gain a more complete understanding of the neural circuit pathology underlying auditory perceptual hypersensitivity. Beyond peripheral injury, sensory hypersensitivity is associated with other conditions such as aging and neurodevelopmental disorders including autism. Thus, insight from this project into the neural signatures of hyperactivity and behavioral hypersensitivity will prove valuable broadly for hearing impairment, other sensory disorders, and related neurological conditions.