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.

项目概要 神经递质催产素 (OXT) 以其社会和生殖作用而闻名，但也获得了广泛的关注。 作为暴露于有害刺激的神经反应的内源性调节剂，人们越来越关注。 激活哺乳动物的神经内分泌和中枢投射的产生 OXT 的神经元 下丘脑，并且这两个群体均已被证明具有镇痛作用。 投射群体通过梨状肌中的目标影响与疼痛相关的行为，例如恐惧调节 而这些细胞抑制敏锐感知和长期记忆的能力。 痛苦经历的积累使它们与疼痛障碍、创伤后的临床治疗高度相关 压力和其他条件下，人们对细胞和电路机制知之甚少。 下丘脑 OXT 神经元影响疼痛处理，或者更一般地说它们如何影响其他疼痛 相关现象。 该项目将利用斑马鱼幼虫提供的实验杠杆来研究通过 OXT 神经元增强感觉运动回路对疼痛刺激的敏感性并促进防御 我们的中心模型是刺激强度是由 OXT 子群中的分级活动编码的。 通过微分投射到脊髓投射神经元（SPN）上并激活或敏化的神经元 OXT 和谷氨酸的释放 我们将通过结合钙成像来检验这一假设， 光遗传学、电生理学和行为学：(1) 确定 OXT 神经元亚群是否 疼痛激活的细胞包括投射到 SPN 上的细胞，以及这些神经元是否特异性介导 (2) 量化OXT和共传的个体贡献 (3)判断是否 谷氨酸和 OXT 释放与尖峰频率的差异耦合使 OXT 神经元能够从 从简单的兴奋性活动模式到高刺激强度下更强的调节性模式。 实验将展示催产素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。