Chaotic Dynamics of Inner Ear Hair Cells

在美国，听力损失影响着大约3000万名患者。由于内耳毛细胞的丢失或损伤可能导致深度耳聋，了解其正常功能的机制是重要的，这是未来临床治疗进展的先决条件。这项研究旨在阐明这种生物传感器是如何工作的，从而知道哪种传感器可以帮助未来研究它是如何失败的。非线性过程和有源放大已被证明是听力极端敏感的关键。虽然许多研究已经探索了各种潜在的放大机制，但确定性或随机噪声的作用相对较少受到关注。因此，该项目是对目前在现场进行的大多数工作的补充，可以提供关于听觉和前庭系统如何在存在波动时实现灵敏度的一些缺失信息。这种方法需要实验和理论研究相结合来解决这个长期悬而未决的问题。PI建议将教育努力与研究计划相结合，向本科生传授与生命系统物理相关的主题。在以前课程的基础上，她将推出一个新课程，让学生了解统计力学和非线性动力学在生物学中广泛开放问题的应用。她还提议开设新的研讨会，旨在将来自不同理论物理领域的科学家和研究听觉系统的生物学家聚集在一起。内耳的毛细胞是生物传感器，可以检测空气或地面振动引起的位移，并将其转换为电信号。它们的响应性关键依赖于一个活跃的过程，该过程放大了由传入声音引起的振荡。活动过程的特征之一，毛细胞束，已经被证明在没有任何输入的情况下表现出极限环振荡，即自发运动。PI假设天生的运动性表现出混沌行为，并建议测试混沌如何影响检测的灵敏度。将在体外获得牛蛙球囊毛细胞的长时间记录，并将应用动力系统理论的分析工具来提取Lyapunov指数，构建Poincare映射，并估计表征运动的Kolmogorov熵。然后毛细胞将受到不同强度和持续时间的机械刺激，以观察外部信号如何影响混乱的状态。药理和电操作也将被用来使细胞处于不同的动态状态。目标是确定这个生物系统是否以及如何利用混沌来提高其检测灵敏度。对发束的被动机械性能的估计表明，它在水中的热波动应该比检测阈值高出几乎一个数量级。PI建议研究噪声在发束反应中的作用，具体地说，它是否有助于检测所施加的信号。她的目标是解释如何在浸泡在水介质中的系统中执行灵敏的机械检测，该系统保持在室温或更高的温度下，因此受到显著的热波动。这项研究将深入了解听觉的基本机制，并为混沌在主动系统探测灵敏度中的作用提供一个通用模型。该项目由物理部的生命系统物理学项目和综合组织系统部的神经簇共同支持。

Hearing loss affects about 30 million patients in United States. Since loss or damage to hair cells of the inner ear can lead to profound deafness, it is important to understand the mechanisms of their proper functioning, as a prerequisite to progress in future clinical treatments. This study is aimed at elucidating how this biological sensor works, knowing which can hence aid in future studies of how it fails. Nonlinear processes and active amplification have been shown to be key to the extreme sensitivity of audition. While many studies have explored the various potential mechanisms of amplification, the role of either deterministic or stochastic noise has received comparatively little attention. This project is hence complementary to most of the work currently performed in the field, and could provide some of the missing information on how the auditory and vestibular systems achieve the sensitivity in the presence of fluctuations. This approach requires a combination of experimental and theoretical studies to address this long-open problem. The PI proposes to combine educational efforts with the research program, to teach undergraduate students topics of relevance for the physics of living systems. Building on prior courses, she will introduce a new class that will expose students to the applications of statistical mechanics and nonlinear dynamics to a broad range of open questions in biology. She also proposes to launch new workshops, aimed at bringing together scientists from different fields of theoretical physics and biologists studying the auditory system.Hair cells of the inner ear are the biological sensors that detect displacements induced by air-borne or ground-borne vibrations and transduce them into electrical signals. Their responsiveness is crucially dependent on an active process that amplifies oscillations induced by the incoming sound. One of the signatures of the active process, hair cell bundles, have been shown to exhibit limit cycle oscillations, spontaneous motion in the absence of any input. The PI hypothesizes that the innate motility exhibits chaotic behavior, and proposes to test how chaos impacts the sensitivity of detection. Long recordings of hair cells of the bullfrog sacculus will be obtained in vitro, and analytic tools from dynamic systems theory will be applied to extract the Lyapunov exponents, construct Poincare maps, and estimate the Kolmogorov entropy characterizing the motion. The hair cells will then be subject to mechanical stimulation of varying intensity and duration, to observe how the chaotic regime is impacted by external signals. Pharmacological and electrical manipulation will also be used to poise the cells in different dynamical states. The goal is to determine whether and how this biological system harnesses chaos to enhance its detection sensitivity. Estimates of the passive mechanical properties of a hair bundle indicate that its thermal fluctuations in water should be almost an order of magnitude higher than the detection threshold. The PI proposes to study the role of noise in the response of hair bundles, and specifically whether it can aid in the detection of applied signals. She aims to explain how sensitive mechanical detection could be performed in a system immersed in an aqueous medium, maintained at room or higher temperatures, and hence subject to significant thermal fluctuations. The study will provide insight into the fundamental mechanism of hearing, as well as providing a general model for the role of chaos in the sensitivity of detection by an active system.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Neural Cluster in the Integrative Organismal Systems Division.