Lauren Janine Donovan
Basic Life Science Research Scientist, Anesthesiology, Perioperative and Pain Medicine
All Publications
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Schwann cell-secreted PGE2 promotes sensory neuron excitability during development.
Cell
2024
Abstract
Electrical excitability-the ability to fire and propagate action potentials-is a signature feature of neurons. How neurons become excitable during development and whether excitability is an intrinsic property of neurons remain unclear. Here, we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce developing somatosensory neurons to express normal levels of genes required for neuronal function, including voltage-gated sodium channels, and to fire action potential trains. Inactivating this signaling pathway in Schwann cells impairs somatosensory neuron maturation, causing multimodal sensory defects that persist into adulthood. Collectively, our studies uncover a neurodevelopmental role for prostaglandin E2 distinct from its established role in inflammation, revealing a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.
View details for DOI 10.1016/j.cell.2024.07.033
View details for PubMedID 39142281
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Senescence of Primary Sensory Neurons as a Driver of Pain in Aging
CHURCHILL LIVINGSTONE. 2024: 43
View details for Web of Science ID 001282167300192
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Determining the Functional Profile of Dorsal Root Ganglion Neurons Driving Osteoarthritis Pain
CHURCHILL LIVINGSTONE. 2024: 11
View details for Web of Science ID 001282167300050
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Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution.
Cell reports
2024; 43 (2): 113683
Abstract
Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. We find that repopulated mouse spinal cord microglia are morphologically distinct from control microglia and exhibit a unique transcriptome. Repopulated microglia from males and females express overlapping networks of genes related to phagocytosis and response to stress. We intersect the identified mouse genes with a single-nuclei microglial dataset from human spinal cord to identify human-relevant genes that may ultimately promote pain resolution after injury. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics.
View details for DOI 10.1016/j.celrep.2024.113683
View details for PubMedID 38261512
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Aging and injury drive neuronal senescence in the dorsal root ganglia.
bioRxiv : the preprint server for biology
2024
Abstract
Aging negatively impacts central nervous system function; however, the cellular impact of aging in the peripheral nervous system remains poorly understood. Aged individuals are more likely to experience increased pain and slower recovery after trauma. Such injury can damage vulnerable peripheral axons of dorsal root ganglion (DRG) neurons resulting in somatosensory dysfunction. One cellular mechanism common to both aging and injury is cellular senescence, a complex cell state that can contribute to the aged pro-inflammatory environment. We uncovered, for the first time, DRG neuron senescence in the context of aging and pain-inducing peripheral nerve injury in young and aged mice. Aged DRG neurons displayed multiple markers of senescence (SA-β-gal, p21, p16, IL6) when compared to young DRG neurons. Peripheral nerve injury triggered a further accumulation of senescent DRG neurons over time post-injury in young and aged DRG. These senescent neurons were dynamic and heterogeneous in their expression of senescence markers, p16, p21, and senescence-associated secretory phenotype (SASP) expression of IL6, which was influenced by age. An electrophysiological characterization of senescence marker-expressing neurons revealed high-firing and nociceptor-like phenotypes within these populations. In addition, we observed improvement in nociceptive behaviors in young and aged nerve-injured mice after treatment with a senolytic agent that eliminates senescent cells. Finally, we confirmed in human post-mortem DRG samples that neuronal senescence is present and increases with age. Overall, we describe a susceptibility of the peripheral nervous system to neuronal senescence with age or injury that may be a targetable mechanism to treat sensory dysfunction, such as chronic pain, particularly in aged populations.
View details for DOI 10.1101/2024.01.20.576299
View details for PubMedID 39829815
View details for PubMedCentralID PMC11741248
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Newly Repopulated Spinal Cord Microglia Exhibit A Unique Transcriptome And Coincide With Sex-Independent Pain Resolution
CHURCHILL LIVINGSTONE. 2023: 5-6
View details for Web of Science ID 000995432100014
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Nociceptor Senescence Following Painful Peripheral Nerve Injury In Young And Aged Mice
CHURCHILL LIVINGSTONE. 2023: 71-72
View details for Web of Science ID 000995432100192
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Sex-distinct microglial activation and myeloid cell infiltration in the spinal cord after painful peripheral injury.
Neurobiology of pain (Cambridge, Mass.)
2022; 12: 100106
Abstract
Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G+neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex in situ hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+microglia are the cellular source of cytokines IL6 and IL1beta after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.
View details for DOI 10.1016/j.ynpai.2022.100106
View details for PubMedID 36531615