Neuromodulatory regulation of synaptic plasticity in spinal nociceptive circuits

脊髓伤害感受回路突触可塑性的神经调节

• 批准号: 10589933
• 负责人: Mark L Baccei
• 金额: $ 60.67万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589933
• 关键词: Adult; Agonist; Brain; Child; Data; Dopamine; Dopamine Receptor; Electric Stimulation; Electrophysiology (science); Environment; Extracellular Signal Regulated Kinases; Fostering; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Generations; Genetic; Human; Immunohistochemistry; In Situ Hybridization; In Vitro; Infant; Injury; Intervention; Investigation; Knowledge; Learning; Life; Link; Long-Term Potentiation; MAPK3 gene; Mediating; Molecular; Mus; Neonatal; Neuromodulator; Neurons; Nociception; Outcome; Output; Pain; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Protocols documentation; Public Health; Receptor Activation; Regulation; Relaxation; Research; Rodent; Sensory; Shapes; Signal Pathway; Signal Transduction; Spinal; Surgical Injuries; Surgical incisions; Synapses; Synaptic plasticity; Testing; Time; Tissues; Vertebral column; Work; antagonist; behavior measurement; chronic pain; design; dorsal horn; druggable target; genetic manipulation; inhibitor; innovation; insight; metabotropic glutamate receptor 5; multidisciplinary; neonatal injury; neonatal surgery; neuroregulation; novel; pain perception; pain sensation; pain sensitivity; permissiveness; pharmacologic; postsynaptic; presynaptic; prevent; receptor; tissue injury; transmission process

Project Summary/Abstract Long-term potentiation (LTP) of primary afferent synapses onto spinal projection neurons (PNs) has been linked to increased pain sensitivity. The timing rules controlling the generation of LTP in adult PNs can be persistently relaxed by neonatal tissue damage, which likely contributes to the ability of early life injury to ‘prime’ nociceptive circuits and thereby exacerbate pain after subsequent insult. In the brain, the temporal window governing this spike timing-dependent plasticity (STDP) is strongly regulated by G protein-coupled receptor (GPCR) signaling evoked by neuromodulators such as dopamine (DA). This raises the possibility that neonatal injury facilitates LTP at primary afferent synapses onto adult PNs, and thereby promotes persistent pain, via long-term changes in spinal neuromodulatory signaling. Unfortunately, it remains unknown how GPCRs influence STDP at sensory synapses onto PNs. As a result, the cellular and molecular mechanisms underlying the increased amplification of ascending nociceptive transmission by the adult dorsal horn during the primed state are poorly understood. The objective of this application is to identify the neuromodulatory signals that promote the activity-dependent strengthening of sensory synapses onto the key output neurons of the spinal nociceptive circuit and contribute to the priming of developing pain pathways after early life injury. The central hypothesis is that ‘non-Hebbian’ LTP at sensory synapses onto spinal PNs is enabled by D1-like (i.e. D1/D5) dopamine receptor activation, occurring in concert with mGluR5-dependent intracellular Ca2+ release and extracellular signal-regulated kinase (ERK) signaling, which is essential for neonatal priming. The rationale of the proposed research is that these studies will identify novel molecular strategies to reduce the signaling gain of the spinal nociceptive network. Guided by strong preliminary data, the central hypothesis will be tested by pursuing the following specific aims: (1) Elucidate how DA receptor activation shapes STDP in PNs; (2) Identify the signaling pathways which cooperate with DA receptors to facilitate LTP in PNs; and (3) Identify the neuromodulators which mediate the priming of spinal nociceptive circuits following neonatal tissue damage. These aims will be accomplished by using a multidisciplinary experimental approach that includes electrophysiological characterization of STDP in PNs combined with both reflexive and non-reflexive behavioral measures of pain. The proposed work is innovative because it will be the first to demonstrate that DA signaling dictates the timing rules governing the plasticity of sensory synapses onto spinal PNs. The outcome of these investigations will be the identification of new spinal mechanisms that augment nociceptive transmission to the brain, and the demonstration that aberrant neuromodulation contributes to the persistent sensitization of spinal nociceptive circuits after early tissue damage. Thus the proposed research is significant because it will provide knowledge needed to design novel interventional strategies to disrupt spinal LTP as a means to alleviate chronic pain and to minimize the long-term consequences of neonatal tissue injury for the developing CNS.

项目总结/摘要 初级传入突触对脊髓投射神经元的长时程增强（LTP）， 与疼痛敏感性增加有关。控制成年PN中LTP产生的时间规则可以 持续放松新生儿组织损伤，这可能有助于早期生命损伤的能力， “启动”伤害感受回路，从而在随后的损伤后加剧疼痛。在大脑中， 控制这种尖峰时间依赖可塑性（STDP）的窗口受到G蛋白偶联的 受体（GPCR）信号传导由神经调节剂如多巴胺（DA）诱发。这就提出了一种可能性， 新生儿损伤促进LTP在初级传入突触到成人PN，从而促进持续性 疼痛，通过脊髓神经调节信号的长期变化。不幸的是，我们仍然不知道 GPCR影响PN上感觉突触的STDP。因此，细胞和分子机制 这是成年人背角上行伤害性传递放大的基础， 对启动状态的了解很少。本申请的目的是鉴定神经调节因子， 信号，促进感觉突触的活动依赖性加强到关键的输出神经元， 脊髓伤害性回路，并有助于启动早期生命损伤后的疼痛通路。 中心假设是，在脊髓PN的感觉突触上的“非Hebbian”LTP是由D1样 (i.e. D1/D5）多巴胺受体激活，与mGluR 5依赖性细胞内Ca 2+协同发生 释放和细胞外信号调节激酶（ERK）信号，这是必要的新生儿启动。的 拟议研究的基本原理是，这些研究将确定新的分子策略，以减少 脊髓伤害感受网络的信号增益。在强有力的初步数据的指导下，中心假设将 通过追求以下具体目标进行测试：（1）阐明DA受体激活如何在STDP中形成STDP。 （2）识别与DA受体协同促进PN中LTP的信号通路;（3） 鉴定介导新生组织后脊髓伤害性回路启动的神经调质 损害这些目标将通过使用多学科实验方法来实现，包括 结合反射性和非反射性行为的PN中STDP的电生理特征 疼痛的措施。拟议的工作是创新的，因为它将是第一个证明DA信号 支配支配感觉突触到脊髓PN上的可塑性的定时规则。成果的 研究将是确定新的脊髓机制，增加伤害性传递到 大脑，并证明异常的神经调节有助于脊髓的持续敏化 早期组织损伤后的伤害感受回路。因此，拟议的研究是重要的，因为它将提供 设计新的介入策略以破坏脊髓LTP作为缓解 慢性疼痛，并最大限度地减少新生儿组织损伤对发育中的CNS的长期后果。