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Harnessing T-junction filtering; bidirectional control of sensory neuron impulse traffic

利用 T 形接头过滤；

基本信息

批准号：
10200908
负责人：
Quinn H Hogan
金额：
$ 46.23万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200908
关键词：
Absence of pain sensation Action Potentials Acute Pain Afferent Neurons Anatomy Animal Disease Models Animals Axon Behavioral Brain imaging Clinical Complement Control Animal Data Degenerative polyarthritis Disease Electrophysiology (science)Esthesia FDA approved Female Foundations Functional Magnetic Resonance Imaging Ganglia Generations Goals In Vitro Inflammation Inflammatory Inflammatory Arthritis Joints Measures Mechanoreceptors Membrane Modality Modeling Molecular Neuraxis Neurogenic Inflammation Neurons Neuropathy Neurostimulation procedures of spinal cord tissue Nociceptors Optics Organ Pain Pain management Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Pharmacology Physiological Population Preparation Process Production Property Rattus Reflex action Regulation Rheumatoid Arthritis Role Sensory Signal Transduction Spinal Ganglia System Testing Therapeutic Tissues Training behavior test calmodulin-dependent protein kinase II chronic pain clinical application conditioned place preference designer receptors exclusively activated by designer drugs dorsal column dorsal horn experimental study in vivo male neuronal cell body neuroregulation novel optogenetics pain relief prevent receptive field sensory system sexual dimorphism spinal nerve posterior root transmission process

项目摘要

Sensory neurons naturally adapt to ongoing stimulation, but harnessing this inherent plasticity for therapeutic purposes has not been explored. The recent clinical observation that dorsal root ganglion field stimulation (GFS) blocks pain, provides a clue that an unrecognized process regulates conduction of impulses through the DRG since exactly the opposite, i.e. production of pain, would be expected. The paradoxical phenomenon of GFS analgesia indicates that our current understanding of peripheral neuron signal transmission is fundamentally insufficient, and that a novel, clinically applicable modality of use-dependent neuronal manipulation awaits discovery. That is the goal of this proposal. Sensory neurons also convey retrograde impulses from the dorsal horn to peripheral tissues, where they trigger inflammation and tissue damage, for instance in rheumatoid arthritis. We will therefore explore bidirectional GFS modulation of both afferent and efferent signal transmission through the DRG. In three Aims, we will test the overall hypothesis that GFS, by triggering action potentials (APs) in the somata of sensory neurons, reduces the intrinsic excitability of their T-junction, which reduces bidirectional propagation of APs through the DRG, and can thereby produce analgesia and block neurogenic inflammation. In Aim 1, we will first develop a rat model in order to lay the groundwork for mechanistic exploration. GFS analgesia will be tested in the setting of neuropathy, and osteoarthritis. To test GFS blockade of retrograde impulses, we will identify GFS effects on joint changes in a model of rheumatoid arthritis. For these experiments, examination will be by behavioral tests and functional magnetic resonance imaging (fMRI) of the brain, examining both male and female rats. In Aim 2, to identify the exact neuronal targets of GFS, we will test GFS activation of sensory neuron somata, and determine which DRG neuronal subtypes are modulated by GFS and at which component (axon vs. soma) this takes place. Aim 3 will employ electrophysiological approaches to directly measure the effects of GFS on functional properties of DRG neurons, in order to identify the mechanism of GFS impulse regulation. Additionally, we will explore the role of CaMKII, and we will compare GFS effects between the various sensory neuron subpopulations. Together, our proposed experiments will establish a mechanistic foundation for a novel regulatory process that governs impulse train transmission in the peripheral nervous system. As molecular and electrical neuromodulatory therapies move forward in the clinical setting, understanding this new regulatory node will have direct translational utility for harnessing an inherent impulse regulating system and applying it to control sensory and peripheral inflammatory disorders.

感觉神经元自然适应持续的刺激，但利用这种固有的可塑性治疗