[R01] Synaptic Function within Mature Central Pain Networks after Neonatal Injury

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2030-06-30

Importo max: 462.342 EUR

Paese: US

Descrizione

Project Summary/Abstract Infants admitted to a neonatal intensive care unit (NICU) regularly experience tissue damage as part of their essential medical care. Preclinical studies have shown that neonatal injury causes a prolonged reorganization of synaptic circuits in the mouse spinal superficial dorsal horn (SDH), enhances neuroimmune signaling in the adult spinal cord, and exacerbates chronic pain following repeat injury later in life via a process called ‘neonatal priming’. Astrocytes are strong candidates to mediate neonatal priming since they are known to tightly regulate synaptogenesis, synaptic pruning, neuronal excitability and neuroinflammation in the CNS, and contribute to the pathogenesis of chronic pain in adults. Unfortunately, nothing is currently known about how neonatal tissue injury shapes the function of immature astrocytes in the developing SDH. It is also unclear if astrocytes catalyze the long-term alterations in synaptic transmission and neuroimmune signaling within the adult SDH following early life injury, and are essential to the subsequent priming of developing pain circuits. The objective of this application is to elucidate the plasticity of developing spinal astrocytes after early life injury and to determine whether astrocytes govern both the persistent functional changes in the mature SDH and neonatal priming. The central hypothesis is that neonatal tissue damage persistently alters the morphology and function of astrocytes in the developing SDH, leading to a disruption in the balance of synaptic excitation vs. inhibition, enhanced capacity for pro-inflammatory signaling and exacerbated chronic pain. The rationale of the proposed research is that by yielding novel insight into the cell types governing the lifelong sensitization of the SDH network following neonatal injury, these studies will lay a conceptual foundation for new interventional strategies to minimize the adverse long-term effects of early life trauma on the maturation of pain pathways in the CNS. Guided by strong preliminary data, the central hypothesis will be tested by pursuing the following specific aims: (1) Determine the influence of early life tissue injury on developing spinal astrocytes; (2) Identify the role of astrocytes in the rewiring of dorsal horn circuits after neonatal injury; and (3) Elucidate the contribution of spinal astrocytes to neonatal priming. These aims will be accomplished by using a multidisciplinary experimental approach that includes intersectional mouse genetics, confocal microscopy, calcium imaging, ex vivo electrophysiology and behavioral assays of pain sensitivity. The proposed work is innovative because it will be the first to reveal the plasticity of astrocytes within developing spinal nociceptive circuits under normal or pathological conditions and to identify their role in neonatal priming. The expected outcome of these investigations will be the identification of astrocytes as a common orchestrator of the myriad p Istituzione: UNIVERSITY OF CINCINNATI PI: Mark L Baccei Progetto: 5R01NS080889-12

Settori: National Institute of Neurological Disorders and Stroke

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