Activity-Dependent Influences on Auditory Circuits

项目摘要 路德维希·范·贝多芬在1801年的一封信中辛酸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，我可怜的健康，在我的车轮上放了一根讨厌的轮子…最后一次 三年来，我的听力变得越来越弱。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。但如果有人大叫，我就受不了。孤零零的天堂 知道我会变成什么样子。“贝多芬自称的疾病可以确定为耳鸣、临界值 移位和听觉过敏症。听力亢进表现为两种截然不同的神经障碍：i)“中毒”， 以令人痛苦的声音触发耳痛的形式，或者ii)一种广泛性的听觉过敏，使甚至 中等强度的声音似乎大得令人不安。第二种，更常见的神经生物学原因， 听力亢进的类型还没有定义。该项目将开发一种噪声诱导的小鼠听力模型。 丢失以揭示导致听觉知觉过敏的神经回路变化。依据目标1进行的研究 将开发一套头部固定的操作型行为分析来跟踪知觉过敏的出现 在噪音引起的高频听力损失之后。AIM 2的研究将使用慢性双光子钙成像 基因定位的听觉皮质兴奋性和抑制性神经元的研究以确定皮质的出现 相对于知觉过敏症的多动症。补充性单一单位电生理学研究将 对比声学刺激和光遗传刺激引起的皮质超兴奋性 脑干直接激活听觉丘脑中的神经元。目标3将检验这样的假设：听觉皮质 通过表达稳定的台阶，超兴奋性是听觉知觉超敏的充要条件 视黄素的功能是暂时诱导或逆转不依赖听力损失的皮质过度兴奋性。研究项目： 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下游影响- 在下行皮质传出神经以及杏仁核和背侧局部胞体中诱导的高兴奋性 下丘的皮质。通过跟踪超兴奋性的精确年表， 听觉通路与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，通常在 听力过敏症患者。这种关联可以通过诱导或逆转皮质来进行因果检验 过度兴奋，并注意到皮质下过度响度增长的潜在逆转。已被占用 总之，这项提议将利用现代神经科学工具对神经细胞进行因果假设检验 一种常见的听力障碍的基础电路改变。感觉过敏也是一种核心表型。 偏头痛以及包括自闭症和脆性X综合征在内的神经发育障碍。识别 过度增强的皮质放大的生物学特征将开辟新的治疗策略，远远 对听力障碍和其他相关神经疾病的影响。

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.