Atlas-Guided Cell-Specific Transcriptomics Identifies Pathway-Level Remodeling of Human Hypothalamic CRH Neurons in Opioid Use Disorder

Barrall, L. R.; Urbanczyk, P. J.; Kluwe-Schiavon, B.; Stertz, L.; Rankothgedera, S.; Castillo, M.; Gunaratne, P. H.; Walss-Bass, C.

doi:10.64898/2026.09.09.749970

bioRxiv · 10.64898/2026.09.09.749970

Atlas-Guided Cell-Specific Transcriptomics Identifies Pathway-Level Remodeling of Human Hypothalamic CRH Neurons in Opioid Use Disorder

Barrall, L. R.·Urbanczyk, P. J.·Kluwe-Schiavon, B.·Stertz, L.·Rankothgedera, S.·Castillo, M.·Gunaratne, P. H.·Walss-Bass, C.

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Abstract

Opioid use disorder (OUD) disrupts hypothalamic stress signaling, yet the molecular state of human paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons remains poorly defined. Using single-nucleus RNA sequencing of 343,819 human hypothalamic nuclei, we applied complementary human HYPOMAP/MapMyCells and mouse PVN Atlas strategies that independently converged on the standardized Allen Brain Map subcluster Splat 410 843, providing cross-atlas validation of a rare CRH-enriched PVN population. Integrated GO, Reactome and KEGG analysis revealed OUD-associated enrichment of synaptic, junctional, cytoskeletal, receptor-signaling and ion transport programs, with relative enrichment of RNA processing, ER Golgi/vesicular, endolysosomal and glycan-related functions in controls. Targeted neuropeptide analysis further identified nominal increases in OXT, GHR, GAL and PRLR and decreases in VIP, AGRP, NPY, CRHBP and CALCR. Together, these findings define a reproducible human PVN CRH population and identify coordinated pathway and neuropeptide remodeling in OUD.

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Barrall, L. R., Urbanczyk, P. J., Kluwe-Schiavon, B., Stertz, L., Rankothgedera, S., Castillo, M., Gunaratne, P. H., Walss-Bass, C.. 2026-09-11. Atlas-Guided Cell-Specific Transcriptomics Identifies Pathway-Level Remodeling of Human Hypothalamic CRH Neurons in Opioid Use Disorder. https://doi.org/10.64898/2026.09.09.749970

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