Neural Mechanisms Underlying the Auditory Phenotype of Mild Traumatic Brain Injury

项目总结/ABSTACT 轻度创伤性脑损伤(MTBI)是一个重大的全球公共卫生问题。在mTBI之后，个人通常 报告听力质量、耳鸣、听觉过敏症和噪声中语音清晰度的困难。为了 了解为什么患者在mTBI后会出现听力障碍，需要结合新的方法 MTBI患者的定量无创生物标志物及其潜在的神经生理学和 解剖上的变化。该提案的主要假设是，许多神经感觉障碍 与mTBI相关的共享与低水平感觉特征编码中断相关的共同根源。在所有的 在感觉系统中，听觉系统对快速、高保真的时间编码提出了最高要求。我们 因此提出脑外伤患者听觉系统异常的时间加工和中枢增益。 动物模型将突出听觉行为后遗症的神经特征，并可能作为 “煤矿里的金丝雀”是指在其他大脑系统中普遍存在的分布式病理生理学。因此， 候选人提出了一项有指导的培训计划，以开发听觉功能障碍的非侵入性生物标志物 MTBI受试者，并在mTBI小鼠模型中确定这些缺陷的神经生物学底物。 应聘者已经组建了一个导师团队，该团队在一系列相关领域拥有专业知识， 建议，包括人类受试者的心理物理学，mTBI小鼠模型，神经生理学测量 听觉时间加工和中枢增益，以及定量耳蜗学组织病理学。通过集成 通过对不同物种的研究进行互补水平的分析，将有可能产生更大的 对颅脑损伤的病理生理学的洞察。在目标1中，候选人将使用听觉的组合 心理物理测试及测试反应后脑电频率的测量 假设mTBI受试者在编码快速时间线索和声强多动方面存在缺陷 相对于控件进行编码。在目标2中，候选人将结合一个小鼠mTBI模型来比较脑电 与细胞外记录的局域场电位和来自下层的单个单位放电的记录相比 丘脑(IC)和听觉皮质(ACTx)来测试是否：1)小鼠表现出类似的听觉时间加工 和在受试者中观察到的中枢获得表型，以及2)异常的时间加工和编码 声强在IC或ACTx中更为普遍。在目标3中，考生将检查感觉和神经 MTBI后小鼠耳蜗的病理变化以及Gria2和Gria2基因转录的变化 Ic和ACTx中Gabra1基因的表达水平。目标3中的这些研究将解决这样一个假设，即监管失调 听觉时间加工和中枢获得与耳蜗性传入神经病和失衡有关 中枢听觉通路中兴奋性和抑制性信号的标志物。K08奖将是一个至关重要的 迈向成为独立的临床医生-科学家的目标的垫脚石。

PROJECT SUMMARY / ABSTACT Mild traumatic brain injury (mTBI) is a major global public health issue. Following mTBI, individuals commonly report difficulties with hearing quality, tinnitus, hyperacusis, and speech-in-noise intelligibility. In order to understand why patients experience auditory dysfunction after mTBI, new approaches are needed that combine quantitative non-invasive biomarkers in mTBI patients with studies of the underlying neurophysiological and anatomical changes. The overarching hypothesis of the proposal is that many of the neurosensory disorders associated with mTBI share a common root related to a disruption of low-level sensory feature coding. Of all the sensory systems, the auditory system places the highest demand on rapid, high-fidelity temporal coding. We therefore propose that abnormal temporal processing and central gain in the auditory system of mTBI patients and animal models would highlight a neural signature of the auditory behavioral sequalae and may serve as the “canary in the coal mine” for distributed pathophysiology occurring more generally in other brain systems. Thus, the Candidate proposes a mentored training plan to develop non-invasive biomarkers of auditory dysfunction in mTBI subjects and to identify the neurobiological substrates for these deficits in a mouse model of mTBI. The Candidate has assembled a mentorship team that has expertise in a range of relevant areas for the proposal, including psychophysics in human subjects, mTBI mouse models, neurophysiological measures of auditory temporal processing and central gain, and quantitative cochlear histopathology. By integrating complementary levels of analysis through the study of different species it will be possible to generate greater insight into the pathophysiology of mTBI. In Aim 1, the Candidate will use a combination of auditory psychophysical tests and measures of the electroencephalography (EEG) frequency following response to test the hypothesis that mTBI subjects show deficits in coding rapid temporal cues and hyperactivity in sound intensity coding relative to controls. In Aim 2, the Candidate will incorporate a mouse mTBI model to compare EEG recordings against extracellular recordings of local field potentials and single unit spiking from the inferior colliculus (IC) and auditory cortex (ACtx) to test whether: 1) mice exhibit a similar auditory temporal processing and central gain phenotype observed in human subjects, and 2) abnormal temporal processing and coding of sound intensity are more prevalent in the IC or ACtx. In Aim 3, the Candidate will examine sensory and neural pathology in the cochlea of mice that have undergone mTBI, as well as transcriptional changes in Gria2 and Gabra1 mRNA levels in the IC and ACtx. These studies in Aim 3 will address the hypothesis that dysregulation of auditory temporal processing and central gain are linked to cochlear afferent neuropathy and imbalanced markers of excitatory and inhibitory signaling in the central auditory pathway. The K08 award will be a crucial stepping-stone toward the goal of developing into an independent clinician-scientist.