Synaptic Function within Mature Central Pain Networks after Neonatal Injury

新生儿损伤后成熟中枢疼痛网络内的突触功能

• 批准号: 9760819
• 负责人: Mark L Baccei
• 金额: $ 36.26万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760819
• 关键词: Adult; Age; Asthma; Automobile Driving; Behavioral; Birth; Brain; Cells; Child; Childhood; Coupled; Data; Development; Dynorphins; Electrophysiology (science); Exhibits; Fiber; Foundations; Funding; Generations; Goals; Hypersensitivity; Immunohistochemistry; Impairment; In Vitro; Infant; Inhibitory Synapse; Injury; Interneurons; Investigation; Knowledge; Life; Long-Term Effects; Mechanics; Mediating; Molecular; Mus; Neonatal; Nervous system structure; Neurobiology; Neurons; Neuropeptides; Nociception; Obesity; Outcome; Output; Pain; Pathologic; Pathway interactions; Population; Posterior Horn Cells; Predisposition; Process; Public Health; Reflex action; Research; Sensory; Severities; Shapes; Signal Transduction; Spinal; Spine pain; Surgical Injuries; Surgical incisions; Synapses; Techniques; Testing; Time; Tissues; Trauma; Work; base; behavior measurement; behavioral study; central pain; chronic pain; critical period; design; developmental neurobiology; dorsal horn; economic cost; experience; genetic approach; innovation; insight; intersectionality; multidisciplinary; neonatal injury; neonatal period; neonate; neural circuit; novel; novel therapeutic intervention; optogenetics; pain reduction; pain sensation; pain sensitivity; patch clamp; postnatal development; prevent; sensory input; synaptic function; synaptic inhibition

Despite growing evidence that tissue damage during a critical period of early life can exacerbate pain severity following subsequent injury, the cellular and molecular mechanisms by which neonatal trauma can ‘prime’ developing nociceptive pathways remain unclear. Furthermore, while inhibitory interneurons in the adult spinal dorsal horn (DH) are known to be comprised of multiple subpopulations which regulate distinct aspects of sensory processing, the classes of inhibitory interneurons that are important for shaping pain sensitivity in the neonate have yet to be identified. Finally, the degree to which neonatal injury primes developing pain circuits by disrupting the maturation of specific subpopulations of inhibitory DH neurons necessary for feedforward inhibition of ascending spinal projection neurons has yet to be elucidated. The long-term goal is to facilitate the design of age-appropriate strategies to treat chronic pain by advancing our understanding of the developmental neurobiology of central nociceptive networks. The objective of this application is to elucidate the consequences of early tissue injury for the maturation of identified inhibitory synaptic circuits within the spinal DH. The central hypothesis is that neonatal tissue damage disrupts the development of primary afferent drive to dynorphin-expressing (DYN) interneurons mediating feedforward inhibition of ascending projection neurons, which contributes to the priming of spinal nociceptive circuits to subsequent injury. The rationale of the proposed research is that by yielding novel insight into the postnatal development of distinct spinal inhibitory circuits under normal and pathological conditions, these studies will lay a conceptual foundation for new therapeutic approaches to restrict the output of the spinal pain network in an age-specific manner and minimize the adverse long-term effects of neonatal injury on the developing CNS. 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) Determine how early tissue damage shapes primary afferent drive to inhibitory interneurons in the developing DH; (2) Identify the DH interneurons which mediate feedforward inhibition of developing spinal projection neurons under normal and pathological conditions; and (3) Identify the inhibitory interneurons in the developing DH whose ability to suppress pain is compromised by neonatal tissue injury. These aims will be accomplished by using a multidisciplinary experimental approach that includes in vitro electrophysiological, optogenetic, chemogenetic, behavioral and immunohistochemical techniques. The outcome of these investigations will be the first insight into how early tissue damage alters the functional organization of inhibitory microcircuits in the developing spinal nociceptive network and thereby diminishes their ability to suppress pain sensation. As a result, the proposed research is significant because it will identify the specific inhibitory synaptic pathways within the spinal DH that must ultimately be restored in order to prevent the exaggerated susceptibility to chronic pain following neonatal tissue damage.

尽管越来越多的证据表明生命早期关键时期的组织损伤会加剧疼痛 随后损伤后的严重程度，新生儿创伤可能的细胞和分子机制 此外，成人中的抑制性中间神经元的“主要”发展伤害感受途径仍不清楚。 已知脊髓背角 (DH) 由多个亚群组成，这些亚群调节不同的方面 感觉处理过程中，抑制性中间神经元的类别对于塑造疼痛敏感性很重要 最后，新生儿损伤引发疼痛的程度尚未确定。 通过破坏特定的抑制性 DH 神经元亚群的成熟来抑制环路 上行脊髓投射神经元的前馈抑制尚未阐明。 通过加深我们对慢性疼痛的理解，促进设计适合年龄的策略来治疗慢性疼痛 本应用的目的是阐明中枢伤害性网络的发育神经生物学。 早期组织损伤对已识别的抑制性突触回路成熟的影响 脊髓 DH 的中心假设是新生儿组织损伤破坏了初级传入神经的发育。 驱动表达强啡肽（DYN）的中间神经元介导上行投射的前馈抑制 神经元，这有助于启动脊髓伤害性回路以应对随后的损伤。 拟议的研究是通过对不同脊柱的出生后发育产生新的见解 正常和病理条件下的抑制回路，这些研究将为 新的治疗方法以特定年龄的方式限制脊柱疼痛网络的输出， 在强有力的指导下，尽量减少新生儿损伤对发育中的中枢神经系统的不利长期影响。 初步数据，将测试中心假设，并通过以下方式实现该应用程序的总体目标 追求以下具体目标：（1）确定早期组织损伤如何塑造初级传入驱动 发育中的 DH 中的抑制性中间神经元；(2) 识别介导前馈的 DH 中间神经元 在正常和病理条件下抑制脊髓投射神经元的发育；以及 (3) 识别 发育中的 DH 中的抑制性中间神经元，其抑制疼痛的能力受到新生儿组织的损害 这些目标将通过使用多学科实验方法来实现，其中包括： 体外电生理学、光遗传学、化学遗传学、行为和免疫组织化学技术。 这些研究的结果将首次深入了解早期组织损伤如何改变功能 抑制性微电路在发育中的脊髓伤害性网络中的组织，从而减少 因此，这项研究具有重要意义，因为它将确定它们抑制疼痛的能力。 脊髓 DH 内的特定抑制性突触通路最终必须恢复，以便 防止新生儿组织损伤后对慢性疼痛的过度敏感性。