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: 10059391
• 负责人: Matthew McGill
• 金额: $ 3.88万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059391
• 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; Hyperactive behavior; 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 Threshold; Pathology; Peripheral; Peripheral Nerves; Persons; Phenotype; Population; Prevalence; Probability; Process; Proxy; Recording of previous events; Reflex action; Reporting; Reproducibility; Retina; Rewards; Sensory; Sensory Disorders; Stimulus; System; Techniques; Testing; Time; Training; Viral; Visual; autism spectrum disorder; base; behavior measurement; cell type; deprivation; driving force; excitatory neuron; hearing impairment; insight; nervous system disorder; neural circuit; 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.

项目摘要/摘要 在感觉系统中，剥夺外围输入与神经补偿性增加有关 感觉皮质水平的兴奋性。通常，这个补偿过程超出了标记，结果 在多动症中以及对感觉刺激的感知过敏。这样的观察有很长的历史 在听觉系统中：噪声引起的对耳蜗的损害与矛盾的皮质有关 多动症和感知异常，例如Hypersusis，一种听觉障碍，其特征是 提高响度到中度强烈的声音。尽管认为皮质多动症 是感知性超敏反应背后的推动力，确切的联系尚不清楚。这是指导的培训 项目将在小鼠中结合慢性行为，两光子成像和光遗传技术 了解行为过敏表型的出现的神经变化 高频噪声引起的听力损失。根据AIM 1的研究将发展两种强迫 评估头部固定小鼠响度的选择任务。这样的行为提供了两个主要的 进步：i）直接评估噪声暴露后的感知性超敏反应，ii） 行为小鼠的慢性成像。 AIM 2的研究将使用听觉的慢性两光子钙成像 皮质纹状体神经元，一种与听觉引导的行为直接相关的定义细胞类型。成像将发生 在被动和任务引进的条件下，既允许频率和强度的全面表征 整个图表上的响应变化，并能够直接比较神经活动的变化与 感知决策。 AIM 3将测试诱导听觉皮质纹状体过度兴奋的假设 在未暴露的对照小鼠中，患有健康的耳蜗足以增加感知的概率 将中等强度的声音分类为大声。皮质纹状体神经元将被转移到进出 使用稳定的步骤功能OPINS暂时诱导稳定和可逆平面的多动态状态 正常，行为小鼠的过度兴奋性。总之，该项目将克服以前的技术限制 为了更完整地了解听觉感知的神经电路病理学 高敏性。除了外周损伤之外，感觉超敏反应与其他条件有关 衰老和神经发育障碍，包括自闭症。因此，从这个项目中的洞察力到神经 多动症和行为超敏反应的签名将证明对听力障碍广泛有价值， 其他感觉障碍和相关的神经系统疾病。