Corticostriatal Contributions to Auditory Perceptual Hypersensitivity

项目摘要/摘要 在整个感觉系统中，外周输入的剥夺与神经的代偿性增加有关 感觉皮层水平的兴奋性。通常，这种补偿过程超出了目标，结果是 多动症伴随着对感官刺激的知觉过敏。这样的观察有很长的历史 在听觉系统中：噪音引起的耳蜗损伤与自相矛盾的大脑皮层有关 多动症和知觉异常，如听觉过敏症，一种以听力障碍为特征的听觉障碍 感觉到的响度增加到中等强度的声音。尽管人们认为大脑皮层的过度活动 是知觉过敏症背后的驱动力，但确切的联系尚不清楚。这是一次指导培训 该项目将结合小鼠的慢性行为、双光子成像和光遗传学技术来 了解以下行为过敏表型出现背后的神经变化 高频噪声引起的听力损失。根据目标1进行的研究将制定一种两种选择的强制 评估头部固定小鼠的响度知觉的选择任务。这样的行为提供了两个主要的 进展：i)直接评估暴露于噪声后的知觉超敏反应，ii)能力 表现良好的小鼠的慢性成像。AIM 2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，一种明确的细胞类型，与听觉引导行为直接相关。将进行成像 在被动和任务忙碌的情况下，都允许充分表征频率和强度 反应的变化，并允许直接比较神经活动的变化与 感性的决策。目标3将检验诱发听觉皮质纹状体过度兴奋性的假设 在未暴露的对照组小鼠中，拥有健康耳蜗者足以增加感知到的 将中等强度的声音归类为响亮。皮质纹状体神经元将被移入和移出 利用稳定阶跃函数OPSINS暂时诱导稳定和可逆面的超活动状态 正常、行为正常的小鼠的过度兴奋。总之，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背后的神经回路病理 过敏症。除了外周损伤，感觉过敏还与其他情况有关，如 衰老和神经发育障碍，包括自闭症。因此，这个项目对神经的洞察 多动症和行为过敏症的特征将被证明对听力障碍有广泛的价值， 其他感觉障碍，以及相关的神经疾病。

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.