Synaptic function within mature central pain networks after neonatal injury

描述（由申请人提供）：虽然组织损伤通常发生在新生儿重症监护治疗期间，并能改变一生的疼痛敏感性，但这种早期损伤是否能引起成熟伤害性通路中突触功能的长期变化仍不清楚。因此，导致新生儿损伤后疼痛敏感性持续改变的细胞和分子机制尚不清楚。长期目标是通过确定新生儿组织损伤如何影响整个发育过程中的伤害感受加工来改善疼痛的临床治疗。该应用程序的总体目标是确定成熟的啮齿动物浅表背角（SDH）网络在早期组织损伤后的变化，这些变化促进了伤害性突触与上行投射神经元的活动依赖性可塑性，上行投射神经元构成脊髓疼痛网络的输出。核心假设是，新生儿组织损伤引起脊髓抑制回路功能的持续缺陷，导致成人I层投射神经元前馈抑制减少，导致伤害性突触对这些细胞的长期增强（LTP）。提出的研究的基本原理是，通过阐明早期组织损伤如何调节突触对成年投射神经元的未来可塑性，这些实验将揭示发展中的脊髓疼痛回路可以“启动”产生更大程度的高兴奋性的潜在机制。在强有力的初步数据的指导下，将对中心假设进行检验，并通过追求以下具体目标来实现本应用的总体目标：(1)确定新生儿组织损伤对成熟I层投射神经元gaba能和甘氨酸能信号传导效率的长期影响；(2)阐明早期组织损伤如何调节成年期脊髓I层投射神经元内感觉输入的整合；(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。这些目标将通过体外电生理、免疫组织化学和通道追踪技术来实现，以表征新生儿组织损伤对成人SDH内突触信号的影响，并确定早期损伤对上升投射神经元内信号处理的总体后果。这些研究的结果将是确定脊髓疼痛网络的突触组织在早期组织损伤后的永久性改变，这种改变会在随后的有害刺激下促进中枢神经系统中上升疼痛信号的放大。因此，该研究具有重要意义，因为它将增强我们对新生儿时期疼痛经历如何调节中枢疼痛通路中伤害性突触可塑性的理解，从而为儿科和成人慢性疼痛状况之间的新联系提供机制见解。

DESCRIPTION (provided by applicant): 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 efficay 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.