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Mian, S. M.

Publications and source records attributed to Mian, S. M..

2 recordsLinked to original sources
bioRxiv2025

Eukaryotic initiation factor 3d Regulates Context-Dependent Pain Hypersensitivity Through the Integrated Stress Response

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a noncanonical cap binding protein implicated in selective mRNA translation under stress conditions. Here, we investigate the contribution of eIF3d to pain processing using a heterozygous eIF3d knockout (eIF3d+/-) mouse model. We first validated this model, confirming substantial reductions in eIF3d mRNA and protein levels in dorsal root ganglia. Baseline assessments revealed no differences in mechanical, thermal, cold, or spontaneous pain behaviors between eIF3d+/- (HET) and eIF3d+/+ (WT) mice, indicating intact basal nociceptive function. In pain models involving peripheral inflammation and metabolic stress, including methylglyoxal injection, IL-6 administration and paw incision, HET mice displayed significantly reduced mechanical and cold hypersensitivity. In contrast, HET mice exhibited increased second phase nocifensive behavior in the formalin test, possibly indicating enhanced central sensitization. Hyperalgesic priming was comparable between HET and WT mice following IL-6 exposure. Experimental autoimmune encephalomyelitis (EAE) induced mice were unaffected by eIF3d reduction. These findings demonstrate that eIF3d selectively modulates nociceptive plasticity under defined stress conditions and suggests a context dependent role in the regulation of inflammatory and central pain sensitization. HighlightsO_LIBaseline mechanical, thermal, cold and spontaneous pain are intact in eIF3d+/-mice C_LIO_LIMethylglyoxal-evoked ISR activation and mechanical pain is blunted in eIF3d+/-mice C_LIO_LIIL-6-evoked mechanical and cold pain are reduced without altered priming C_LIO_LIMechanical hypersensitivity is reduced in eIF3d+/- mice with paw incision C_LIO_LIEAE pain is unaltered but increased pain in phase II formalin pain in eIF3d+/-mice C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/695844v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@26d9aforg.highwire.dtl.DTLVardef@9d7350org.highwire.dtl.DTLVardef@fdbabeorg.highwire.dtl.DTLVardef@1ef1074_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2025

Spatial transcriptomic profiling of human paravertebral sympathetic chain ganglia reveals diabetes-induced neuroplasticity

The paravertebral sympathetic chain ganglia (SCG) are autonomic ganglia critical for regulating the "fight-or-flight" response. Symptoms of sympathetic dysfunction are prevalent in diabetes, affecting up to 90% of patients. The molecular and cellular composition of the human SCG and its alteration in diabetes remains poorly defined. To address this gap, we performed spatial transcriptomic profiling of lumbar SCGs from diabetic and non-diabetic organ donors. We identified 3 three distinct neuronal populations, two noradrenergic (NA1 and NA2) and one cholinergic (CHO), based on tyrosine hydroxylase (TH) and SLC18A3 expression, respectively. We also characterized 9 non-neuronal populations consisting of Schwann cells, immune cells, fibroblasts, adipocytes, and endothelial cells. In diabetic SCGs, we observed a significant loss of myelinating Schwann cells and a phenotypic shift of cholinergic neurons toward a noradrenergic identity. Additionally, diabetes was associated with a significant reduction in the transcripts of vasodilatory neuropeptides, such as VIP and CALCA, suggesting a mechanism for impaired vascular control. Upstream regulator analysis highlighted altered neurotrophic signaling in diabetes, with enhanced NGF/TRKA and diminished BDNF/TRKB activity, potentially driven by target-derived cues. Comparison between SCG and dorsal root ganglia (DRG) neurons revealed ganglia-specific genes, like SCN3A and NPY (SCG) versus SCN10A and GPX1 (DRG), offering specific therapeutic targets for autonomic dysfunction or pain. Our findings provide a transcriptomic characterization of human SCG, revealing molecular signatures that underlie diabetic autonomic dysfunction. This work lays a foundation for the development of therapies to restore sympathetic function and avoid unintended autonomic effects in the development of analgesics. Significance StatementAutonomic dysfunction affects up to 90% of people with diabetes, yet the human sympathetic nervous system remains poorly molecularly defined. To address this gap, we present a spatial transcriptomic profile of the human sympathetic chain ganglia (SCG), revealing how diabetes affects the human autonomic nervous system. We show that diabetes shifts the cholinergic neuronal population to a noradrenergic phenotype and reduces vasodilation neuropeptide expression, potentially explaining impaired vascular control and thermoregulation. Comparative analysis of sympathetic and sensory ganglia reveals distinct gene profiles that may inform novel therapeutic strategies. These findings offer critical insight into the molecular drivers of diabetic autonomic neuropathy and lay the groundwork for safer, more precise treatments that selectively modulate autonomic or sensory function in chronic disease.

neuroscience↗