Cellular and circuit mechanisms enabling oxytocinergic control of pain defense

细胞和电路机制使催产素能控制疼痛防御

• 批准号: 10394865
• 负责人: ADAM D DOUGLASS
• 金额: $ 33.36万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394865
• 关键词: Acute; Affect; Amygdaloid structure; Analgesics; Anatomy; Animal Model; Animals; Architecture; Attention; Automobile Driving; Axon; Behavior; Behavioral; Brain; Calcium; Cells; Clinical Treatment; Coupling; Data; Dependence; Electrophysiology (science); Elements; Exposure to; Frequencies; Glutamates; Heterogeneity; Hypothalamic structure; Image; Individual; Measures; Mediating; Modeling; Nervous system structure; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Nociceptors; Optics; Output; Oxytocin; Pain; Pain Disorder; Pain management; Perception; Phase; Physiological; Play; Population; Process; Property; Role; Sensorimotor functions; Shapes; Signal Transduction; Spinal; Stimulus; Structure; Testing; Zebrafish; behavioral response; behavioral sensitization; conditioned fear; experience; experimental study; hindbrain; human model; improved; insight; interest; long term memory; neural circuit; novel; optogenetics; pain perception; pain processing; piriform cortex; post-traumatic stress; relating to nervous system; reproductive; response; sensory input; social; transmission process

Project Summary The neurotransmitter oxytocin (OXT) is well known for its social and reproductive roles, but has also gained increasing attention as an endogenous regulator of the neural response to pain. Exposure to noxious stimuli activates both neuroendocrine and centrally-projecting OXT-producing neurons in the mammalian hypothalamus, and both populations have been shown to exert analgesic effects. Additionally, the centrally- projecting group influences pain-related behaviors such as fear conditioning through targets in the piriform cortex and the amygdala. While the ability of these cells to dampen the acute perception and long-term memory of painful experience makes them highly relevant to the clinical treatment of pain disorders, post-traumatic stress, and other conditions, very little is known about the cellular and circuit mechanisms by which hypothalamic OXT neurons influence pain processing, or more generally how they might affect other pain- related phenomena. This project will exploit the experimental leverage offered by the larval zebrafish to investigate the means by which OXT neurons enhance the sensitivity of a sensorimotor circuit to painful stimuli and promote defensive behaviors. Our central model is that stimulus intensity is encoded by graded activity in a subpopulation of OXT neurons which project onto and activate or sensitize spinal projection neurons (SPNs) through the differential release of OXT and glutamate. We will test this hypothesis by using a combination of calcium imaging, optogenetics, electrophysiology, and behavior to: (1) Determine whether the subpopulation of OXT neurons activated by pain includes cells that project onto the SPNs, and whether those neurons specifically mediate OXT’s effects on defensive behavior; (2) Quantify the individual contributions of OXT and co-transmitted glutamate to SPN activation and behavioral sensitization during noxious experience; (3) Determine whether differential coupling of glutamate and OXT release to spike frequency enables the OXT neurons to switch from a simple, excitatory mode of activity to a stronger, modulatory mode at high stimulus intensities. These experiments will show how the basic cellular and circuit properties of oxytocinergic neurons shape the behavioral response to pain in a vertebrate model.

项目摘要 神经递质催产素（OXT）以其社会和复制角色而闻名，但也已获得 作为神经对疼痛反应的内源性调节剂的注意力越来越大。暴露于有害的刺激 激活哺乳动物中的神经内分泌和中央注射牛的神经元 下丘脑和两个种群都显示出镇痛作用。此外，中央 投影组影响与疼痛相关的行为，例如通过梨状靶标进行恐惧调节 皮质和杏仁核。这些细胞能够抑制急性感知和长期记忆力 痛苦的经历使它们与疼痛障碍的临床治疗高度相关，创伤后 压力和其他条件，对细胞和电路机制知之甚少 下丘脑牛神经元会影响疼痛的处理，或更普遍地影响其他疼痛 - 相关现象。 该项目将利用幼虫斑马鱼提供的实验杠杆来调查手段 牛神经元增强了感觉运动电路对疼痛刺激的敏感性并促进防御性 行为。我们的中心模型是，刺激强度是通过在oxt亚群中分级活性编码的 通过差异向投射并激活或激活或敏感的脊柱投射神经元（SPN）的神经元 释放OXT和谷氨酸。我们将通过使用钙成像的组合来检验该假设， 光遗传学，电生理学和行为：（1）确定OXT神经元的亚群是否是否 被疼痛激活包括将投射到SPN上的细胞，以及这些神经元是否专门介导 OXT对防御行为的影响； （2）量化OXT和共同传输的个人贡献 在有害的经历期间，谷氨酸对SPN激活和行为敏感性； （3）确定是否 谷氨酸和oxt释放以尖峰频率的差异耦合使牛神经元从 在高刺激强度下，一种简单，令人兴奋的活动模式，以更强的调节模式。这些 实验将显示氧气神经元的基本细胞和电路特性如何塑造 脊椎动物模型中对疼痛的行为反应。