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.

项目摘要 路德维希·范·贝多芬（Ludwig van Beethoven 对一个朋友说：“但是那个嫉妒的恶魔，我悲惨的健康，让我的方向盘上说话了……最后 三年我的听证会变得越来越弱。我的耳朵昼夜嗡嗡作响。 有时，我几乎无法听到一个轻声说话的人……但是如果有人喊着，我就无法忍受。一个人天堂 知道我会变成什么。”贝多芬的自称疾病可以识别为耳鸣 分别转移和超值。 Hyper Acusis表现为两种不同的神经系统疾病：i）“毒性”， 以令人难以置信的声音触发耳痛或ii）普遍的听觉超敏反应的形式 中等强烈的声音似乎很大。第二个，更常见的神经生物学原因， 超源类型尚未定义。该项目将开发噪声引起的听力的鼠标模型 揭示神经回路变化的损失会导致听觉感知性超敏反应。根据目标1的研究1 将开发一套固定的操作行为测定法，以跟踪感知性超敏反应的出现 噪声引起的高频听力损失。 AIM 2的研究将使用慢性2光子钙成像 在听觉皮层中具有遗传靶向兴奋和抑制性神经元的形象，以查明皮质的出现 相对于感知性超敏反应的多动症。互补的单个单位电生理研究将 用声刺激与光遗传学刺激引起的对比皮质过度刺激性，绕过耳朵和光遗传学刺激 脑干直接激活听觉丘脑中的神经元。 AIM 3将测试听觉皮层的假设 通过表达稳定的步骤，过度兴奋性是必要的，足以进行听觉感知性超敏反应 功能动作蛋白暂时诱导或反向皮质过度兴奋性，独立于听力损失。研究 AIM 4将通过跟踪噪声的出现来解决多余中央增益的下游效应 - 降低皮质效率以及杏仁核和背部的局部细胞体引起的过度兴奋性 下丘的皮层。通过跟踪在范围内外的过度兴奋性的精确年表 听觉途径以及声音触发的防御行为（例如冻结），可以识别 感觉可塑性与动画和压力的疾病之间的直接联系，通常在 患有超顾问的人。可以通过诱导或逆转皮质进行随意测试该关联 过度兴奋，并注意到过度响度生长的皮质下制造商的潜在逆转。拍摄 该建议将共同利用现代神经科学工具来对神经元进行因果假设检验 电路变化是普通听力障碍的基础。感觉超敏反应也是 偏头痛以及神经发育障碍，包括自闭症和脆弱的X综合征。识别 过度强化皮质扩增的生物学特征将开启新的治疗策略，并具有广泛的治疗 对听力障碍和其他相关神经系统疾病的影响。