Robust criticality in hair bundles

发束中的鲁棒临界性

• 批准号: 9269058
• 负责人: Andrew R. Milewski
• 金额: $ 4.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269058
• 关键词: Address; Affect; American; Auditory; Automobile Driving; Behavior; Biological; Biophysics; Calcium; Categories; Cells; Cochlea; Country; Detection; Discrimination; Disease; Ear; Ensure; Evaluation; Exhibits; Exposure to; Feedback; Frequencies; Generic Drugs; Hair; Hair Cells; Hearing; Hearing Aids; Ion Channel; Loudness; Mechanics; Mediating; Modeling; Nature; Organ; Organelles; Performance; Pharmacology; Physiologic pulse; Process; Property; Public Health; Rana catesbeiana; Side; Signal Transduction; Stimulus; System; Training; Validation; Work; aged; biological systems; cellular transduction; design; driving force; experience; experimental study; hearing impairment; inhibitor/antagonist; insight; mathematical model; novel; operation; predictive modeling; pressure; receptor; response; simulation; sound

PROJECT SUMMARY One in eight Americans aged twelve years and older—roughly 30 million people—suffers some degree of hearing loss. Hearing loss is broadly characterized as conductive, sensorineural, or mixed. The second of these categories encompasses the majority of people with hearing impairment and most frequently results from damage to hair cells, the cells in our ears responsible for detecting sound waves. Addressing this significant public-health concern requires a thorough understanding of the healthy operation of the hair cell and its signal- detection apparatus, the hair bundle. Our sense of hearing boasts exquisite sensitivity, precise frequency discrimination, and a broad dynamic range. A dynamic instability known as a Hopf bifurcation is thought to underlie these impressive features. Systems that exhibit a bifurcation demonstrate a qualitative change in behavior when a parameter of the system reaches its critical value. In hair bundles, this parameter might be calcium concentration or the external load applied to the bundle. Crossing a Hopf bifurcation incites spontaneous oscillations in a previously quiescent system. Just before this transition, when the system is on the verge of oscillating, small-amplitude stimuli are greatly enhanced. Analogously to a public address system turned up to the point of instability, our hearing derives its impressive features from this phenomenon. However, this enhanced response can occur for only the narrow range of parameter values that poise the system near the bifurcation. As a result, minuscule changes in certain parameters can compromise a hair bundle’s ability to detect sound. This poses a challenge to biological systems: How can hair cells exert tight control over parameters to ensure operation in close proximity to the bifurcation? This study seeks to answer this question from a novel perspective. Rather than achieving precise control over parameters, hair cells may employ a mechanism that broadens the region of influence of the dynamical instability. By widening the range of parameter values over which it can attain the desired level of performance, such a mechanism would render signal detection by a hair cell more robust. Evaluation of this hypothesis will be undertaken by first developing mathematical models of hair cell dynamics endowed with the proposed mechanism. Validation of these models will then be sought experimentally by delivering a variety of mechanical stimuli to hair bundles. These experiments will provide a means both to interrogate hair bundles for specific behaviors predicted by the model, and to identify potential effectors of the proposed mechanism. In addition to furthering our insight into how hair cells robustly detect signals, this work will deepen our understanding of the mechanisms responsible for the loss of auditory acuity that we experience following exposure to excessively loud sounds.

项目概要 八分之一的 12 岁及以上美国人（大约 3000 万人）患有某种程度的疾病 听力损失大致可分为传导性听力损失、感音神经性听力损失或混合性听力损失。 这些类别涵盖了大多数有听力障碍的人，并且最常见的原因是 毛细胞（我们耳朵中负责检测声波的细胞）受损，解决这一重大问题。 公共卫生问题需要彻底了解毛细胞的健康运作及其信号- 检测装置，发束。 我们的听觉拥有精湛的灵敏度、精确的频率辨别力和宽广的动态范围。 被称为 Hopf 分岔的动态不稳定性被认为是这些令人印象深刻的特征的基础。 当系统的参数发生变化时，表现出分岔的系统表现出行为的质变 在发束中达到其临界值，该参数可能是钙浓度或外部负载。 施加到束上时，穿过 Hopf 分岔会激发先前静止的自发振荡。 就在这种转变之前，当系统处于振荡边缘时，会出现小幅度刺激。 类似于公共广播系统达到了不稳定的程度，我们的听力得到了极大的增强。 然而，这种增强的反应只能发生在这种现象中。 使系统接近分叉的参数值范围较窄，结果是微小的变化。 某些参数可能会损害发束检测声音的能力，这对生物学提出了挑战。 系统：毛细胞如何对参数进行严格控制，以确保在接近系统的情况下运行 分叉？ 本研究试图从一个新颖的角度回答这个问题，而不是实现精确控制。 在参数上，毛细胞可能采用一种机制来扩大动力学的影响范围 通过扩大可以达到所需性能水平的参数值范围， 这种机制将使毛细胞的信号检测更加稳健。 首先开发毛细胞动力学的数学模型，最终提出了 然后将通过提供各种机械装置来进行实验验证这些模型。 这些实验将提供一种方法来询问发束的特定情况。 模型预测的行为，并识别所提出机制的潜在效应器。 这项工作将加深我们对毛细胞如何稳健地检测信号的了解 过度暴露于环境中导致听觉敏锐度丧失的机制 响亮的声音。