Activity-Dependent Influences on Auditory Circuits

对听觉回路的活动依赖性影响

• 批准号: 10375528
• 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/10375528
• 关键词: Acoustic Stimulation; Acoustics; Address; Amygdaloid structure; Anxiety; Anxiety Disorders; Auditory; Auditory Perception; Auditory area; Axon; Behavior; Behavioral; Behavioral Assay; Biological; Brain Stem; Bypass; Calcium; Cells; Chronic; Chronology; Correlation Studies; Disease; Dorsal; Ear; Earache; Electrophysiology (science); Equilibrium; Exhibits; Fiber; Fragile X Syndrome; Freezing; Friends; Fright; 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; Parvalbumins; Pathology; Pathway interactions; Perception; Persons; Phenotype; Photometry; Preparation; Process; Reporting; Resolution; Sensorineural Hearing Loss; Sensory; Stimulus; Stress; Structure; System; Testing; Therapeutic; Tinnitus; Ursidae Family; Work; auditory pathway; auditory thalamus; behavior test; cell type; comorbidity; density; excitatory neuron; experimental study; hearing impairment; hippocampal pyramidal neuron; inhibitory neuron; insight; millisecond; mouse model; nervous system disorder; neural circuit; neural correlate; noise exposure; normal hearing; noxacusis; optogenetics; relating to nervous system; social; sound; tool; treatment strategy; 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.

项目摘要 路德维希货车贝多芬在1801年的一封信中尖锐地表达了听力损失的感知和社会负担 给一个朋友说，“但是那个嫉妒的恶魔，我可怜的健康，在我的轮子上放了一个讨厌的发言......最后一个 三年来我的听力越来越弱。我的耳朵日夜嗡嗡作响。 有时候我几乎听不到一个人轻声说话......但如果有人大声喊叫，我就受不了了。 我知道我会变成什么样。”贝多芬自我描述的疾病可以确定为耳鸣，阈值 移位和听觉过敏。听觉过敏表现为两种不同的神经系统疾病：i）“伤害性聋”， 以痛苦的声音引发的耳朵疼痛的形式，或ii）广泛的听觉过敏， 中等强度的声音听起来很大，让人不舒服。第二种更常见的神经生物学原因， 听觉过敏的类型尚未被定义。本项目将开发一种噪声诱导听力的小鼠模型 损失揭示神经回路的变化，导致听觉感知过敏。根据目标1开展的研究 将开发一套头部固定的操作性行为分析，以跟踪感知超敏反应的出现 噪音引起的高频听力损失。目标2中的研究将使用慢性双光子钙成像 基因靶向的兴奋性和抑制性神经元在听觉皮层，以查明出现皮层 相对于知觉超敏性的多动。补充的单单位电生理学研究将 对比声刺激引起的皮质过度兴奋与绕过耳朵的光遗传刺激， 脑干直接激活听觉丘脑中的神经元。目标3将检验听觉皮层 过度兴奋是听觉知觉超敏反应的必要和充分条件，通过表达稳定的步骤 功能视蛋白暂时诱导或逆转皮质过度兴奋独立于听力损失。研究 目标4将通过跟踪噪声的出现来解决过度中心增益的分布式下游效应- 在下行皮质传出神经以及杏仁核和背侧核的局部细胞体中诱导过度兴奋 下丘皮质。通过追踪脑内和脑外兴奋过度的精确时间表， 听觉通路以及声音触发的防御行为，如冻结，将有可能识别 感觉可塑性与焦虑和压力障碍之间的直接联系， 有hyperacusis的人这种关联可以通过诱导或逆转皮质 过度兴奋，并注意到过度响度增长的皮层下标记的潜在逆转。采取 总之，这项提案将利用现代神经科学工具对神经系统进行因果假设检验。 造成听力障碍的电路变化。感觉超敏反应也是一种核心表型， 偏头痛以及神经发育障碍，包括自闭症和脆性X综合征。识别 过度放大皮质的生物学特征将开辟新的治疗策略， 对听力障碍和其他相关神经系统疾病的广泛影响。