Corticostriatal Contributions to Auditory Perceptual Hypersensitivity

皮质纹状体对听觉感知超敏反应的贡献

• 批准号: 10436889
• 负责人: Matthew McGill
• 金额: $ 2.35万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436889
• 关键词: Acoustic Trauma; Acoustics; Address; Aging; Animal Model; Auditory; Auditory area; Auditory system; Basal Ganglia; Behavior; Behavioral; Calcium; Chronic; Cochlea; Corpus striatum structure; Decision Making; Development; Disease; Environment; Esthesia; Evaluation; Frequencies; Growth; Head; Hearing problem; High-Frequency Hearing Loss; Human; Hyperactivity; Hyperacusis; Hypersensitivity; Image; Injury; Label; Lead; Lesion; Link; Loudness; Loudness Perception; Maps; Measures; Mentors; Motor; Mus; Neurodevelopmental Disorder; Neurologic; Neurons; Noise; Noise-Induced Hearing Loss; Opsin; Pain; Pain Threshold; Pathology; Peripheral; Peripheral nerve injury; Persons; Phenotype; Population; Prevalence; Probability; Process; Proxy; Recording of previous events; Reflex action; Reporting; Reproducibility; Retina; Rewards; Sensory; Sensory Deprivation; Sensory Disorders; Stimulus; System; Techniques; Testing; Time; Training; Viral; Visual Cortex; auditory deprivation; autism spectrum disorder; base; behavior measurement; cell type; deprivation; driving force; excitatory neuron; hearing impairment; insight; nervous system disorder; neural circuit; noise exposure; normal hearing; optogenetics; relating to nervous system; response; sensory cortex; sensory input; sensory stimulus; sensory system; somatosensory; sound; training project; two-photon

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.

项目概要/摘要 在感觉系统中，外周输入的剥夺与神经元的代偿性增加有关。 感觉皮层水平的兴奋性。通常，这种补偿过程会超出标准，导致 多动症以及对感觉刺激的知觉过敏。这种观察有着悠久的历史 在听觉系统中：噪音引起的耳蜗损伤与矛盾的皮质有关 多动和知觉异常，例如听觉过敏，一种以听觉障碍为特征的听觉障碍 感知响度增加至中等强度的声音。尽管人们相信皮质过度活跃 是知觉超敏背后的驱动力，但明确的联系尚不清楚。本次辅导培训 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 了解以下行为超敏反应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 进行的研究将开发一种有两种选择的强制方法 评估头部固定小鼠的响度感知的选择任务。这种行为提供了两个主要 进展：i）直接评估噪声暴露后的知觉超敏反应，以及 ii）做事的能力 行为小鼠的慢性成像。目标 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，一种与听觉引导行为直接相关的明确细胞类型。将进行成像 在被动和任务参与条件下都可以全面表征频率和强度 整个音调主题图的反应变化，并能够直接比较神经活动的变化 感性决策。目标 3 将检验诱发听觉皮质纹状体过度兴奋的假设 在具有健康耳蜗的未暴露对照小鼠中，足以增加感知的可能性 将中等强度的声音归类为大声。皮质纹状体神经元将移入和移出 使用稳定的阶跃函数视蛋白暂时诱导稳定且可逆的平面的过度活跃状态 正常行为小鼠的过度兴奋。总而言之，该项目将克服以前的技术限制 更全面地了解听觉感知背后的神经回路病理学 超敏反应。除了外周损伤之外，感觉过敏还与其他病症相关，例如 衰老和神经发育障碍，包括自闭症。因此，从这个项目中深入了解神经网络 多动症和行为过敏的特征将被证明对听力障碍具有广泛的价值， 其他感觉障碍以及相关的神经系统疾病。