Biology subjects

Mydugolam, H.

Publications and source records attributed to Mydugolam, H..

4 recordsLinked to original sources

bioRxiv2025

A molecular map of the human spinal dorsal and ventral horn defines arrangement of neuronal types and glial sex differences

The spinal cord is the gateway for somatosensory and nociceptive information to the brain and a key locus for sensory-motor integration. Studies in mice have advanced our understanding of spinal cord circuitry, and transcriptomic studies have begun to characterize the human spinal cord; however, major gaps in knowledge persist. We conducted single-nucleus sequencing of lumbar spinal cord tissue from 11 adult organ donors and annotated spinal cord cell types with high resolution spatial transcriptomics. We identified 34 spatially and transcriptionally defined neuronal classes and detected sex-specific cell types and states across multiple glial populations. Electrophysiological recordings from dorsal horn neurons revealed firing patterns for neuronal subtypes and group I mGluR-dependent plasticity. Our work defines previously unknown aspects of human spinal cord molecular anatomy and physiology.

neuroscience↗

bioRxiv2025

Peripheral nerve-targeting and pain-promoting transcriptomic signatures in early Guillain-Barr&eacute syndrome

Guillain-Barre syndrome (GBS) is an autoimmune disorder that causes weakness, sensory loss, autonomic dysfunction, and chronic neuropathic pain. The mediators responsible for driving early autoimmune injury in the most common GBS variant, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), remain incompletely understood. We performed single-cell and bulk RNA sequencing on peripheral blood mononuclear cells collected from early untreated AIDP-variant GBS patients and healthy controls to comprehensively deduce leukocyte transcriptome alterations and predict disease- and pain-driving interactions between pathogenic leukocytes and peripheral nervous system cells. We found that classical, intermediate, and non-classical monocytes were expanded and upregulated genes associated with type I and II interferons, JAK/STAT signaling, and NLRP3 inflammasome engagement. CD8+ T cells were highly proliferative and likewise upregulated JAK/STAT signaling. CD4+FOXP3+ regulatory T cells upregulated PRDM1 and CD74 in a signature that may indicate functional exhaustion. A subpopulation of highly activated intermediate monocytes upregulated genes related to angiogenesis and oncostatin M. Differential expression-based cell-cell interaction analysis between GBS leukocytes, Schwann cells, and sensory neurons predicted engagement of ligand-receptor pairs with nerve integrity and pain functions, including epiregulin, interferon-beta, adrenomedullin, clusterin, IL-6, IL-15, and CCL4. Functional validation demonstrated that CCL4 sensitizes human sensory neurons in vitro. These results unearth molecular interactions by which specific leukocyte populations in AIDP-variant GBS may participate in peripheral nerve injury and drive neuropathic pain. Many of these targets may be amenable to therapeutic modulation using available approved and investigational drugs, potentially providing drug repurposing opportunities.

neuroscience↗

bioRxiv2025

Life-long hydroxyurea treatment decreases chronic sickle cell disease pain

Chronic sickle cell disease (SCD) pain mechanisms remain critically understudied, even though more than 50% of patients develop this symptom as their disease progresses. Despite high face validity, there are critical gaps in transgenic SCD mouse model characterization and implementation that must be addressed in order to increase the translational relevance of these animals. First, it is unclear when the chronic pain phenotype first develops in these mice. Second, there are no studies that have measured chronic pain in animals following standard-of-care drug regimens. Herein, we address both of these gaps by performing reflexive pain behavior tests in hydroxyurea-treated Townes HbSS and HbAA mice from postnatal day 10 to 6 months of age. Hydroxyurea (HU), a compound that increases circulating levels of fetal hemoglobin (HbF), is a life-long therapy prescribed to individuals with SCD beginning as early as age 9 months. Here, we demonstrate that chronic mechanical hypersensitivity develops in Townes HbSS mice between P21-P28, a time frame that follows the HbF-to-HbS switch. When initiated at birth, HU treatment limits the extent of chronic mechanical pain development in HbSS mice. HU analgesic effects can be attributed to decreased innate immune tone in the periphery; life-long HU treatment decreases circulating monocyte counts in HbSS mice and reverses sensitization of TRPA1, a lipopolysaccharide receptor, in HbSS nociceptors. In conclusion, these studies provide additional support for early implementation of HU in SCD disease management, and furthermore, identify the LPS-TRPA1 signaling axis as a novel analgesic target for chronic SCD pain.

physiology↗

bioRxiv2025

Type I interferons enhance human dorsal root ganglion nociceptor excitability and induce TRPV1 sensitization

Type I interferons (IFNs) are critical cytokines for antiviral defense and are linked to painful inflammatory diseases like rheumatoid arthritis and neuropathic pain in humans. Studies in rodent models demonstrate a direct action on sensory neurons in the dorsal root ganglion (DRG) to promote hyperexcitability but rodent behavioral results are conflicting with some reports of pro-nociceptive actions and others of anti-nociception. Given the role of type I IFNs in human disease, we sought to clarify the action of action of IFN- and IFN-{beta} on human DRG (hDRG) nociceptors. We found that IFN receptor subunits IFNAR1 and IFNAR2 are functionally expressed by these neurons and their engagement induces canonical STAT1 signaling and non-canonical MAPK activation as measured by increased phosphorylation of the cap-binding protein eIF4E by MNK1/2 kinases. Using patch clamp electrophysiology, Ca2+-imaging, and multi-electrode arrays we demonstrate that IFN- and -{beta} increase the excitability of hDRG neurons with short (30 min) and long-term (24-48 h) exposure and prolong the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. Our studies support the conclusion that type I IFNs are pronociceptive when they interact with hDRG nociceptors in the periphery.

neuroscience↗