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：对于我们的生存而言，这是一个必不可少的意义，它使我们能够浏览物理世界。对于简单的日常活动，例如喂养和敷料，而是更复杂的社交互动，例如交配，结合和成功的儿童养育，这一点至关重要。尽管进行了数十年的研究，但触摸敏感性的分子和细胞机制在很大程度上尚不清楚。这项研究的长期目标是使用Merkel细胞神经突配合物作为哺乳动物的机械感觉信号传导的模型来阐明接触接收机制。该应用的目的是测试Merkel-Cell突触活动是否参与SAI响应的产生。默克尔细胞与皮肤的感觉传入形成柔和的受体，从而缓慢适应I型（SAI）反应。 SAI的反应被认为可以介导依靠歧视性触摸来识别和操纵物体的哺乳动物中的高触觉。长期以来，已经提出，默克尔细胞是通过兴奋性神经传递将感觉信息传递到皮肤传入的机械感知细胞。另外，默克尔细胞可能是通过神经传递调节机械敏感SAI传入的感觉输出的辅助细胞。超微结构和分子研究表明，默克尔细胞与SAI传入突触。大量潜在的神经递质与默克尔细胞有关，包括谷氨酸，5-羟色胺，ATP，Met-Enkephalin等。但是，功能研究在这些神经递质的参与方面产生了矛盾的结果。此外，经过一个多世纪的研究，直接证明默克尔细胞具有功能突触。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起SAI传入AIM 1中的动作电位1将测试是否需要从默克尔细胞中释放突触囊泡对接触式诱发的SAI反应是必需的。我将记录SAI传入在小鼠中的活性，其默克尔细胞表达破伤风神经毒素轻链（Tent），这是突触囊泡释放的抑制剂。 AIM 2将测试Merkel-Cell突触活动是否足以在SAI传入中引起动作潜力，如果可以的话，可以识别潜在的兴奋性神经递质。由于默克尔细胞和SAI传入在皮肤中紧密并置，因此触摸刺激不能用于独立激活每种细胞类型的原位。为了打破此障碍，在AIM 2中，我使用默克尔细胞中光门控离子通道通道Ropopsin-2（ChR2）的选择性表达。这使我能够测试具有光的默克尔细胞的选择性激发是否会引起SAI传入中的动作电位。