Activity-Dependent Influences on Auditory Circuits

对听觉回路的活动依赖性影响

• 批准号: 10611996
• 负责人: Daniel B. Polley
• 金额: $ 60.13万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611996
• 关键词: Acoustic Stimulation; Acoustics; Amygdaloid structure; Anxiety; Anxiety Disorders; Auditory; Auditory Perception; Auditory area; Axon; Behavior; Behavioral; Behavioral Assay; Biological; Brain Stem; Bypass; Calcium; Cells; Chronic; Chronology; Compensation; Correlation Studies; Disease; Dorsal; Ear; Earache; Electrophysiology (science); Equilibrium; Exhibits; Fiber; Fragile X Syndrome; Freezing; Friends; Fright; Frustration; Growth; Head; Health; Hearing; Hearing problem; High-Frequency Hearing Loss; Hyperactivity; Hyperacusis; Hypersensitivity; Image; Impairment; Individual; Inferior Colliculus; Lateral; Letters; Link; Loudness; Loudness Perception; Measures; Mediating; Membrane; Methods; Migraine; Modeling; Modernization; Mood Disorders; Mus; Neurobiology; Neurodevelopmental Disorder; Neurons; Neurosciences; Noise; Noise-Induced Hearing Loss; Opsin; Pain; Parvalbumins; Pathology; Pathway interactions; Perception; Persons; Phenotype; Photometry; Preparation; Process; Reporting; Resolution; Sensorineural Hearing Loss; Sensory; Stimulus; Stress; Structure; System; Testing; Therapeutic; Tinnitus; Work; auditory pathway; auditory thalamus; autism spectrum disorder; behavior test; cell type; comorbidity; density; excitatory neuron; experimental study; forging; hearing impairment; hippocampal pyramidal neuron; inhibitory neuron; insight; millisecond; mouse model; nervous system disorder; neural; neural circuit; neural correlate; noise exposure; normal hearing; novel therapeutic intervention; optogenetics; social; sound; tool; two-photon

Project Summary Ludwig van Beethoven poignantly expressed the perceptual and social burden of hearing loss in an 1801 letter to a friend stating, “But that jealous demon, my wretched health, has put a nasty spoke in my wheel…for the last three years my hearing has become weaker and weaker. My ears continue to hum and buzz day and night. Sometimes I can scarcely hear a person who speaks softly…but if anyone shouts I can’t bear it. Heaven alone knows what is to become of me.” Beethoven’s self-described maladies can be identified as tinnitus, threshold shift and hyperacusis, respectively. Hyperacusis presents as two distinct neurological disorders: i) “noxicusis”, in the form of excruciating sound-triggered ear pain or ii) a generalized auditory hypersensitivity that makes even moderately intense sounds seem uncomfortably loud. The neurobiological causes of this second, more common, type of hyperacusis have yet to be defined. This project will develop a mouse model of noise-induced hearing loss to reveal neural circuit changes that cause auditory perceptual hypersensitivity. Studies pursuant to Aim 1 will develop a suite of head-fixed operant behavioral assays to track the emergence of perceptual hypersensitivity following noise-induced high-frequency hearing loss. Studies in Aim 2 will use chronic 2-photon calcium imaging of genetically targeted excitatory and inhibitory neurons in auditory cortex to pinpoint the emergence of cortical hyperactivity relative to perceptual hypersensitivity. Complementary single unit electrophysiology studies will contrast cortical hyperexcitability elicited with acoustic stimuli versus optogenetic stimuli that bypass the ear and brainstem to directly activate neurons in the auditory thalamus. Aim 3 will test the hypothesis that auditory cortex hyperexcitability is necessary and sufficient for auditory perceptual hypersensitivity by expressing stabilized step function opsins to temporarily induce or reverse cortical hyperexcitability independent of hearing loss. Studies in Aim 4 will address the distributed downstream effects of excess central gain by tracking the emergence of noise- induced hyperexcitability in descending cortical efferents as well as local cell bodies in the amygdala and dorsal cortex of the inferior colliculus. By tracking the precise chronology of hyperexcitability within and beyond the auditory pathway alongside sound-triggered defensive behaviors such as freezing, it will be possible to identify a direct link between sensory plasticity and disorders of anxiety and stress that are commonly observed in individuals with hyperacusis. This association can be causally tested by inducing or reversing cortical hyperexcitability and noting a potential reversal in subcortical makers of excess loudness growth. Taken together, this proposal will leverage modern neuroscience tools to perform causal hypothesis testing on neural circuit changes that underlie a common hearing disorder. Sensory hypersensitivity is also a core phenotype of migraine as well as neurodevelopmental disorders including Autism and Fragile X syndrome. Identifying the biological signatures of over-powered cortical amplification would open up new treatment strategies, with far- ranging implications for hearing impairment and other related neurological disorders.

项目概要 路德维希·范·贝多芬在 1801 年的一封信中深刻地表达了听力损失的感知和社会负担 对一位朋友说：“但是那个嫉妒的恶魔，我受损的健康，在我的车轮上放了一个令人讨厌的辐条……最后一次 三年来，我的听力越来越弱，我的耳朵日夜不停地嗡嗡作响。 有时我几乎听不到一个人轻声说话……但如果有人大声喊叫，我一个人就无法忍受。 知道我会变成什么样子。”贝多芬自称的疾病可以被认为是耳鸣、阈值。 听觉过敏分别表现为两种不同的神经系统疾病：i)“毒性”， 以令人难以忍受的声音引发的耳痛或 ii) 普遍的听觉过敏，甚至使 中等强度的声音听起来令人不舒服，这是第二种更常见的神经生物学原因。 听力过敏的类型尚未确定，该项目将开发噪音诱发听力的小鼠模型。 无法揭示导致听觉感知超敏性的神经回路变化 根据目标 1 进行的研究。 将开发一套头部固定操作行为分析来追踪知觉超敏反应的出现 目标 2 中的噪声引起的高频听力损失研究将使用慢性 2 光子钙成像。 听觉皮层中基因靶向的兴奋性和抑制性神经元，以查明皮质的出现 与知觉过敏相关的多动症的补充单单元电生理学研究将。 对比声刺激引起的皮质过度兴奋与绕过耳朵的光遗传学刺激 目标 3 将测试听觉皮层的假设。 通过表达稳定的步长，过度兴奋对于听觉感知超敏反应是必要且充分的 功能视蛋白暂时诱导或逆转皮质过度兴奋性，与听力损失无关。 目标 4 将通过跟踪噪声的出现来解决超额中央增益的分布式下游影响。 诱导下行皮质传出神经以及杏仁核和背侧局部细胞体的过度兴奋 通过跟踪下丘皮质内部和外部的过度兴奋的精确时间顺序。 听觉通路以及声音触发的防御行为（例如冻结），将有可能识别 感觉可塑性与焦虑和压力障碍之间存在直接联系，常见于 患有听觉过敏的个体可以通过诱导或逆转皮质来进行因果关系测试。 过度兴奋并注意到皮层下过度响度增长的潜在逆转。 总之，该提案将利用现代神经科学工具对神经网络进行因果假设检验 常见听力障碍背后的电路变化也是感觉过敏的核心表型。 偏头痛以及神经发育障碍，包括自闭症和脆性 X 综合征。 过度强大的皮质放大的生物特征将开辟新的治疗策略，具有深远的意义。 对听力障碍和其他相关神经系统疾病有广泛的影响。