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，早期生命关键时期的组织损伤会加剧疼痛 继发性损伤后的严重程度，新生儿创伤的细胞和分子机制 “最重要的”发展伤害性感受的途径仍不清楚。此外，虽然成体中的抑制性中间神经元 众所周知，脊髓背角由多个亚群组成，它们调节不同的方面 在感觉加工中，抑制中间神经元的类别对于形成疼痛敏感性是重要的 新生儿的身份尚未确定。最后，新生儿损伤引发疼痛的程度 通过干扰特定亚群的抑制性脱氢酶神经元的成熟来实现 脊髓上行投射神经元的前馈抑制尚不清楚。长期目标是 促进设计适合年龄的治疗慢性疼痛的策略，通过促进我们对 中枢伤害性神经网络的发育神经生物学。本申请的目的是阐明 早期组织损伤对脑内已识别的抑制性突触回路成熟的影响 脊椎型卫生署。中心假设是新生儿组织损伤干扰初级传入神经的发育。 对强啡肽表达中间神经元的驱动介导对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。其基本原理是 拟议的研究是通过对不同脊椎的出生后发育产生新的见解 在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，并 将新生儿损伤对发育中的中枢神经系统的不良长期影响降至最低。以Strong为指导 初步数据，中心假设将得到检验，这项申请的总体目标将通过 追求以下具体目标：(1)确定早期组织损伤如何形成初级传入驱动 发育中的脱氢酶中间神经元；(2)识别参与前馈反应的脱氢酶中间神经元 在正常和病理条件下抑制发育的脊髓投射神经元；以及(3)确定 发育中的中间神经元抑制疼痛的能力受到新生组织的影响 受伤。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、光遗传学、化学遗传学、行为学和免疫组织化学技术。这个 这些研究的结果将是对早期组织损伤如何改变功能的第一次洞察 在发育中的脊髓伤害性网络中组织抑制微电路，从而减少 它们抑制痛感的能力。因此，拟议的研究具有重要意义，因为它将确定 脊髓中特定的抑制性突触通路，最终必须恢复才能 防止新生儿组织损伤后对慢性疼痛的过度敏感。