Synaptic function within mature central pain networks after neonatal injury

项目总结/摘要 虽然组织损伤通常发生在新生儿重症监护治疗期间， 在整个生命的敏感性，这种早期损伤是否会引起突触功能的长期变化， 成熟的伤害感受途径仍然未知。因此，细胞和分子机制， 导致新生儿损伤后疼痛敏感性的持续变化仍不清楚。很长的- 长期目标是通过确定新生儿组织损伤如何影响疼痛， 整个发育过程中的伤害性处理。此应用程序的总体目标是确定更改 在成熟的啮齿动物浅表背角（SDH）网络中，早期组织损伤后， 活动依赖性可塑性在伤害性突触上升投射神经元，这构成了 脊髓疼痛网络的输出。中心假设是新生儿组织损伤引起持续性 脊髓抑制回路功能的缺陷，导致成年人的前馈抑制减少 板层I投射神经元，导致伤害性感受神经元的长时程增强（LTP） 突触连接到这些细胞上这项研究的基本原理是，通过阐明早期组织 损伤调节了成年投射神经元突触的未来可塑性，这些实验将 揭示了潜在的机制，通过这种机制，发育中的脊髓疼痛回路可以被“启动”，以产生更大的 在以后的年龄损伤后的过度兴奋的程度。在强大的初步数据的指导下，中央 假设将得到检验，本申请的总体目标将通过以下具体措施实现 目的：（1）探讨新生儿组织损伤对GABA能和甘氨酸能治疗效果的影响 （2）阐明早期组织损伤如何调节神经元的功能， 成年期脊髓I层投射神经元内感觉输入的整合;和（3）确定 新生儿损伤改变成熟脊髓投射神经元突触可塑性的程度。这些目标将 通过使用体外电生理学、免疫组织化学和束追踪技术来完成， 表征新生组织损伤对成年SDH内突触信号传导的影响，并确定 早期损伤对上行投射神经元内信号处理的总体后果。的 这些研究的结果将是识别突触组织中的永久性改变 脊髓疼痛网络的早期组织损伤，促进上行疼痛的放大 在随后的伤害性刺激后的中枢神经系统信号。因此，本文的研究具有重要的意义 因为它将增强我们对中枢疼痛通路中伤害性突触可塑性的理解， 在新生儿时期的痛苦经历调制，从而提供机械洞察力， 儿童和成人慢性疼痛状况之间的新联系。

Project Summary/Abstract Although tissue damage commonly occurs during neonatal intensive care treatment and can alter pain sensitivity throughout life, whether such early injuries can evoke long-term changes in synaptic function within mature nociceptive pathways remains unknown. As a result, the cellular and molecular mechanisms which contribute to the persistent alterations in pain sensitivity following neonatal injury are still unclear. The long- term goal is to improve the clinical treatment of pain by determining how neonatal tissue injury influences nociceptive processing throughout development. The overall objective of this application is to identify changes within the mature rodent superficial dorsal horn (SDH) network following early tissue damage that facilitate activity-dependent plasticity at nociceptive synapses onto ascending projection neurons, which constitute the output of the spinal pain network. The central hypothesis is that neonatal tissue damage evokes persistent deficits in the function of spinal inhibitory circuits which result in decreased feed-forward inhibition of adult lamina I projection neurons, leading to an enhancement of long-term potentiation (LTP) at nociceptive synapses onto these cells. The rationale of the proposed research is that by elucidating how early tissue damage modulates the future plasticity of synapses onto adult projection neurons, these experiments will reveal potential mechanisms by which developing spinal pain circuits can be "primed" to produce a greater degree of hyperexcitability following injuries at later ages. Guided by strong preliminary data, the central hypothesis will be tested and the overall objective of this application achieved by pursuing the following specific aims: (1) Identify the prolonged effects of neonatal tissue injury on the efficacy of GABAergic and glycinergic signaling onto mature lamina I projection neurons; (2) Elucidate how early tissue damage modulates the integration of sensory input within spinal lamina I projection neurons during adulthood; and (3) Determine the extent to which neonatal injury alters synaptic plasticity in mature spinal projection neurons. These aims will be accomplished by using in vitro electrophysiological, immunohistochemical, and tract-tracing techniques to characterize the effects of neonatal tissue damage on synaptic signaling within the adult SDH and determine the overall consequences of early injury for signal processing within ascending projection neurons. The outcome of these investigations will be the identification of permanent alterations in the synaptic organization of spinal pain networks following early tissue damage which promote the amplification of ascending pain signals in the CNS following subsequent noxious stimulation. As a result, the proposed research is significant because it will enhance our understanding of how nociceptive synaptic plasticity in central pain pathways is modulated by painful experience during the neonatal period and thus provide mechanistic insight into the emerging link between pediatric and adult chronic pain conditions.