The Neural Basis of Ocular Sensations

摘要 眼睛干燥和配戴隐形透镜常引起异物感。这种异常的机械感觉 与“眼睑擦拭器上皮病”（LWE）有关，这是一种由对眼睑的机械损伤引起的疾病。 睑缘结膜（也称为“眼睑刮片”）。然而，潜在的神经感觉机制 仍然难以捉摸我们最近发现，一群初级感觉神经元的表达， MrgprD选择性地支配眼睑擦拭器，并且对剪切力敏感。该提案旨在确定 表达MrgprD的感觉纤维是否介导眼机械感觉并调节流泪。在Aim中 1，我们将表征眼睑中表达MrgprD的感觉纤维的神经支配和机械敏感性 雨刷使用遗传标记和轴突追踪方法，我们将进行详细的解剖分析， 眼睑擦拭器中表达MrgprD的感觉纤维的组织和末端超微结构。此外，我们将 通过传导传导性传导，测试眼睑擦拭器中表达MrgprD的感觉纤维是否可以被剪切力激活。 体内钙显像这些研究将有助于阐明表达MrgprD的感觉纤维在眼神经系统中的作用。 机械感觉在目标2中，我们将进一步确定表达MrgprD的感觉纤维是否感知剪切力， 在眼球运动中用力。我们将确定是否基因消融或药理学沉默， 表达MrgprD的神经元增强剪切力诱导的眼机械感觉。这 这项研究将提供关于眼睑擦拭器机械感觉的神经感觉机制的见解。在目标3中，我们 确定眼睑擦拭器的机械感觉是否调节流泪以维持眼部的润滑 面具体地说，我们将研究是否消融MrgprD表达的感觉纤维影响基底神经元的功能。 流泪和机械性流泪。此外，我们将测试是否化学发生激活 眼睑擦拭器中表达MrgprD的感觉纤维促进流泪。最后，我们将确定 表达MrgprD的感觉纤维的药理学活化是一种潜在的治疗策略， 干眼症条件下流泪。这些研究将揭示眼机械感觉的神经基础 与生理性泪液蒸发和眼表病理性干燥相关， 这对我们理解眼机械感觉作为一种保护机制及其临床意义产生了重大影响。 干眼症治疗中应用。

ABSTRACT Dry eyes and contact lens wear often cause foreign body sensation. This abnormal mechanosensation is associated with “Lid Wiper Epitheliopathy” (LWE), a condition induced by the mechanical damage to the marginal palpebral conjunctiva (also known as “lid wiper”). However, the underlying neurosensory mechanism remains elusive. We recently found that a population of primary sensory neurons defined by the expression of MrgprD selectively innervates the lid wiper and is sensitive to shear force. This proposal aims to determine whether MrgprD-expressing sensory fibers mediate ocular mechanosensation and regulate lacrimation. In Aim 1, we will characterize the innervations and mechanosensitivity of MrgprD-expressing sensory fibers in the lid wiper. Using genetic labeling and axonal tracing approaches, we will perform detailed anatomical analysis of organization and terminal ultrastructure of MrgprD-expressing sensory fibers in the lid wiper. In addition, we will test whether MrgprD-expressing sensory fibers in the lid wiper can be activated by shear force by conducting ex vivo calcium imaging. These studies will shed light on the role of MrgprD-expressing sensory fibers in ocular mechanosensation. In Aim 2, we will further determine whether MrgprD-expressing sensory fibers sense shear force during eye movements. We will determine whether genetic ablation or pharmacological silencing of MrgprD-expressing neurons alleviates the ocular mechanosensation induced by enhanced shear force. This study will provide insight on the neurosensory mechanism of the lid wiper mechanosensation. In Aim 3, we will determine whether the lid wiper mechanosensation regulates lacrimation to maintain the lubrication of the ocular surface. Specifically, we will examine whether ablation of MrgprD-expressing sensory fibers affects basal lacrimation and mechanically-induced lacrimation. Furthermore, we will test whether chemogenetic activation of MrgprD-expressing sensory fibers in the lid wiper promotes lacrimation. Finally, we will determine whether pharmacological activation of MrgprD-expressing sensory fibers is a potential therapeutic strategy for promoting lacrimation under dry eye conditions. These studies will reveal the neural basis of ocular mechanosensation associated with physiological tear evaporations and pathological dryness of the ocular surface, which will have a significant impact in our understanding of ocular mechanosensation as a protective mechanism and its clinical implication in dry eye treatments.