The role of macrophages in neonatal nociceptive priming

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Project Summary/Abstract: Early life insults have the ability to “prime” the somatosensory system (neonatal priming) which changes the way peripheral stimuli are perceived. This can lead to worse outcomes after an injury later in life. As a result, significant clinical problems such as chronic pain and increased opioid use can occur. A better understanding of how acute neonatal injury facilitates the transition to chronic pain later in life is therefore crucial. Previous work has begun to dissect the central neuronal and immune components that contribute to neonatal nociceptive priming, but the peripheral component is vastly understudied. It is known however that a peripheral input is required for the “priming” effect to be induced and more recent data suggests that immune cells are necessary for altering nociception uniquely in neonates compared to older subjects. Our preliminary work confirms recent literature that neonates in which macrophages are ablated, do not demonstrate injury-induced mechanical hypersensitivity. Interestingly, macrophages are also unique in neonates as they have the ability to retain epigenetic modifications from early life stimulation. This epigenetic vulnerability in immature macrophages may provide a mechanism that drives neonatal nociceptive priming. This project will aim to answer the major gaps in the literature by providing a better understanding of how the peripheral immune system retains a memory of early life injury to effect nociception later in life. We will test the central hypothesis that the activation of neonatal macrophages following acute injury alters their epigenetic regulation of neuroimmune signals which is critical for the development of neonatal priming. We will test this through a series of experiments that interrogate the necessity of macrophages through knockout strategies, sufficiency of macrophages through adoptive transfer, and determine epigenetic mechanisms within macrophages that may underlie this phenomenon. Specific Aim 1 uses our ex vivo electrophysiological recording preparations, assays of behavioral sensitivity, and measures of inflammation in mice with depletion (MaFIA mice) or adoptive transfer of macrophages to determine the effects of neonatal incision on peripheral sensitization and nociceptive priming. Specific Aim 2 first uses unbiased sequencing strategies in macrophages, and then evaluates whether macrophage specific expression of the developmentally regulated histone deacytalase, SIRT1, modulates neonatal nociceptive priming. In order to address these questions, a team of researcher mentors have been assembled to provide expertise in sensory neuroscience and neonatal nociception (Dr. Jankowski, primary sponsor), immunology (Dr. Deepe, co- sponsor) and epigenetics (Dr. Kottyan, co-sponsor) who will instruct and help me with these specific research studies. This team of mentors will also provide all of the necessary academic and scientific development to further my career in the neurosciences. Collectively, this project will provide impactful information on neonatal priming and allow me to establish a solid foundation for an independent career in pain biology.