Synaptic Transmission In Mammalian Cutaneous Touch Receptors

哺乳动物皮肤触觉感受器的突触传递

基本信息

批准号：
8648005
负责人：
Srdjan Maksimovic
金额：
$ 4.22万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-02 至 2014-06-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648005
关键词：
ATP Receptors Action Potentials Address Antigen-Presenting Cells Area Behavior Cells Child Rearing Cleaved cell Code Complex Cutaneous Dense Core Vesicle Discrimination Environment Epidermis Esthesia Gated Ion Channel Generations Glutamate Receptor Glutamates Goals Hair Cells Human In Situ Investigation Ion Channel Knowledge Labyrinth Light Mammals Mechanics Mechanoreceptor Cell Mechanoreceptors Mediating Membrane Merkel Cells Methionine Enkephalin Modeling Molecular Monitor Motor Mus Nerve Neurites Neurobiology Neurotransmitters Output Pain Partner in relationship Perception Peripheral Physiological Play Preparation Process Proteins Reading Receptor Cell Research Role Sensory Serotonin Shapes Signal Pathway Signal Transduction Site Skin Social Interaction Sterile coverings Stimulus Synapses Synaptic Transmission Synaptic Vesicles Tactile Testing Tetanus Toxin Texture Time Touch sensation Training Ursidae Family Vesicle base braille cell type cellular microvillus cellular transduction design feeding immunoreactivity inhibitor/antagonist instrument keratinocyte light gated mouse model neurotransmission neurotransmitter release programs public health relevance receptive field receptor research study response selective expression serotonin receptor skills somatosensory tetanospasmin voltage

项目摘要

DESCRIPTION (provided by applicant): The importance of touch is undeniable: it is an essential sense for our survival that allows us to navigate the physical world. It is vital not onl for simple daily activities such as feeding and dressing, but also for more complicated social interactions such as mating, bonding and successful child rearing. Despite decades of research, the molecular and cellular mechanisms underlying touch sensitivity are largely unknown. The long- term goal of this research is to elucidate mechanisms of touch reception using the Merkel cell-neurite complex as a model for mechanosensory signaling in mammals. The objective of this application is to test whether Merkel-cell synaptic activity is involved in generation of SAI responses. Merkel cells together with cutaneous sensory afferents form gentle-touch receptors, which generate slowly adapting type I (SAI) responses. SAI responses are thought to mediate high tactile acuity in mammals that rely on discriminative touch to recognize and manipulate objects. It has long been proposed that Merkel cells are mechanosensory cells that transduce sensory information to cutaneous afferents via excitatory neurotransmission. Alternatively, Merkel cells might be accessory cells that modulate sensory output of mechanosensitive SAI afferents via neurotransmission. Ultrastructural and molecular studies suggest that Merkel cells synapse with SAI afferents. A plethora of potential neurotransmitters have been associated with Merkel cells, including glutamate, serotonin, ATP, met-enkephalin and others. However, functional studies have yielded contradictory results regarding the involvement of these neurotransmitters. Moreover, a direct demonstration that Merkel cells have functional synapses is still lacking after more than a century of investigation. This application's central hypothesisis that Merkel cells release excitatory neurotransmitters to elicit action potentials in SAI afferents Aim 1 will test whether synaptic vesicle release from Merkel cells is necessary for touch-evoked SAI responses. I will record SAI afferent's activity in mice whose Merkel cells express tetanus neurotoxin light chain (TeNT), an inhibitor of synaptic vesicle release. Aim 2 will test whether Merkel-cell synaptic activity is sufficient to elicit action potentials in SAI afferents and, if so will identify underlying excitatory neurotransmitters. Since Merkel cells and SAI afferents are tightly juxtaposed in the skin, touch stimuli cannot be used to independently activate each cell type in situ. To break this barrier, in Aim 2 I use selective expression of the light-gated ion channel channelrhodopsin-2 (ChR2) in Merkel cells. This allows me to test if selective excitation of Merkel cells with light evokes action potentials in SAI afferents.

描述（由申请人提供）：触摸的重要性是不可否认的：它是我们生存的基本感觉，使我们能够驾驭物质世界。它不仅对于喂养和穿衣等简单的日常活动至关重要，而且对于交配、亲密关系和成功抚养孩子等更复杂的社交互动也至关重要。尽管经过了数十年的研究，触摸敏感度背后的分子和细胞机制在很大程度上仍是未知的。这项研究的长期目标是利用默克尔细胞神经突复合物作为哺乳动物机械感觉信号传导的模型来阐明触摸接收机制。本应用的目的是测试 Merkel 细胞突触活动是否参与 SAI 反应的生成。默克尔细胞与皮肤感觉传入细胞一起形成轻柔的触觉受体，产生缓慢适应的 I 型 (SAI) 反应。 SAI 反应被认为可以调节哺乳动物的高触觉敏锐度，而哺乳动物依靠辨别性触摸来识别和操纵物体。长期以来，人们一直认为默克尔细胞是机械感觉细胞，可通过兴奋性神经传递将感觉信息转变成皮肤传入神经。或者，默克尔细胞可能是辅助细胞，通过神经传递调节机械敏感 SAI 传入的感觉输出。超微结构和分子研究表明默克尔细胞与 SAI 传入神经发生突触。大量潜在的神经递质与默克尔细胞有关，包括谷氨酸、血清素、ATP、甲硫氨酸脑啡肽等。然而，关于这些神经递质的参与，功能研究得出了相互矛盾的结果。此外，经过一个多世纪的研究，仍然缺乏直接证明默克尔细胞具有功能性突触的证据。该应用的中心假设是默克尔细胞释放兴奋性神经递质以引发 SAI 传入动作电位。目标 1 将测试默克尔细胞释放突触小泡是否对于触摸诱发的 SAI 反应是必要的。我将记录默克尔细胞表达破伤风神经毒素轻链 (TeNT)（一种突触小泡释放抑制剂）的小鼠中 SAI 传入神经的活动。目标 2 将测试默克尔细胞突触活动是否足以引发 SAI 传入神经的动作电位，如果是的话，将识别潜在的兴奋性神经递质。由于默克尔细胞和 SAI 传入细胞在皮肤中紧密并置，因此触摸刺激不能用于在原位独立激活每种细胞类型。为了打破这一障碍，在目标 2 中，我使用了默克尔细胞中光门控离子通道通道视紫红质 2 (ChR2) 的选择性表达。这使我能够测试用光选择性激发默克尔细胞是否会诱发 SAI 传入神经的动作电位。