The Neural Basis of Ocular Sensations

摘要 干眼和戴隐形眼镜经常会引起异物感。这种反常的机械感觉 与“雨刷上皮病”(LWE)有关，这是一种由眼部机械损伤引起的疾病 眼睑边缘结膜(也称为“眼睑刮水器”)。然而，潜在的神经感觉机制 仍然难以捉摸。我们最近发现，一组初级感觉神经元由表达的 MRGPRD选择性地支配盖子雨刷，对剪切力很敏感。这项提案旨在确定 表达mrgprD的感觉神经纤维是否参与眼球机械感觉和泪液调节。在AIM 1、我们将描述表达mrgprD的感觉纤维在眼盖内的神经支配和机械敏感性。 雨刷。使用基因标记和轴突追踪方法，我们将进行详细的解剖分析 雨刷中表达mrgprD的感觉纤维的组织和末梢超微结构。此外，我们还将 测试雨刷中表达mrgprD的感觉神经纤维是否能在剪切力作用下通过传导 活体钙成像。这些研究将阐明表达mrgprD的感觉神经纤维在眼部的作用。 机械感应。在目标2中，我们将进一步确定表达mrgprD的感觉纤维是否感觉到剪切。 在眼球运动过程中的力量。我们将确定是基因消融还是药物沉默 表达mrgprD的神经元可减轻由剪切力增强引起的眼球机械感觉。这 研究将为了解雨刷机械感觉的神经感觉机制提供洞察力。在《目标3》中，我们将 确定眼睑刮水器机械感应器是否调节泪水，以维持眼睛的润滑性 浮出水面。具体地说，我们将检查切断表达mrgprD的感觉纤维是否会影响基底 撕裂和机械诱导的撕裂。此外，我们将测试化学生成激活是否 在眼睑刮水器中表达mrgprD的感觉纤维促进泪水分泌。最后，我们将确定是否 药物激活表达mrgprD的感觉纤维是一种潜在的促进 在干眼的情况下流泪。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有关，这将有 对我们理解眼机械感觉作为一种保护机制及其临床的重大影响 这意味着干眼症的治疗。

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.