{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T16:56:42Z","timestamp":1776358602333,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,13]]},"group-title":"Neuroscience","reference-count":81,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Simulated spaceflight perturbs multiple organ systems, yet the integrated impact of spaceflight-relevant stressors on the immune-gut-brain axis remains poorly defined. We used a ground-based model combining hindlimb unloading (HU) with low-dose ionizing radiation (IR; 50 or 100cGy) to quantify neuropathology, peripheral immune phenotypes, intestinal barrier integrity, and behavioral performance in male and female C57BL\/6 mice. HU and\/or IR induced region-selective neurodegenerative changes consistent with axonal injury across the cortex and major white-matter tracts. In the somatosensory cortex, MAP-2+ neurons were reduced and SMI-312-labeled axonal injury increased, lowering the intact-to-dystrophic axonal area ratio. Long-range fiber pathways (corpus callosum, cingulate gyrus, external capsule) showed robust axonal damage accompanied by gliosis, with elevated Iba-1+ microglia and GFAP+ astrocytes most prominent after HU+IR (100cGy). Peripheral immunophenotyping revealed a sustained, sex-dependent innate inflammatory bias, with expanded CD11b+ myeloid cells and increased TNF-\u03b1+ myeloid activation after IR and IR+HU, alongside maladaptive T-cell polarization despite largely unchanged total CD8+ and CD4+ frequencies. In parallel, the gut exhibited architectural remodeling and barrier failure, including altered mucin profiles, reduced ZO-1 tight-junction labeling, and increased CD45+ leukocyte infiltration across the jejunum, ileum, and colon. Behavioral assays demonstrated sex-dependent deficits spanning affective, motor, and cognitive domains, including increased anxiety- and depressive-like behaviors, impaired rotarod performance, reduced recognition memory, and less efficient spatial strategies. Overall, these findings identify a sex-dependent immune-gut-brain vulnerability in which combined HU and low-dose IR drive gut barrier breakdown and immune imbalance that coincide with neuroinflammatory axonopathy and measurable neurobehavioral dysfunction.<\/jats:p>","DOI":"10.64898\/2026.04.09.717543","type":"posted-content","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T23:20:13Z","timestamp":1776122413000},"source":"Crossref","is-referenced-by-count":0,"title":["Simulated spaceflight disrupts the immune-gut-brain axis and drives sex-dependent neuroinflammation, axonal injury, and behavioral deficits"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-3358","authenticated-orcid":false,"given":"Marissa","family":"Burke","sequence":"first","affiliation":[{"name":"Center for Neuroregeneration and Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX"},{"name":"Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5905-9758","authenticated-orcid":false,"given":"G\u00f6knur","family":"Kara","sequence":"additional","affiliation":[{"name":"Center for Neuroregeneration and Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1902-7882","authenticated-orcid":false,"given":"Morgan","family":"Holcomb","sequence":"additional","affiliation":[{"name":"Center for Neuroregeneration and Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1850-1642","authenticated-orcid":false,"given":"Christopher","family":"Mason","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6174-4113","authenticated-orcid":false,"given":"Sonia","family":"Villapol","sequence":"additional","affiliation":[{"name":"Center for Neuroregeneration and Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX"},{"name":"Department of Neuroscience in Neurological Surgery, Weill Cornell Medical College, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041609101416000_2026.04.09.717543v1.1","unstructured":"Cucinotta, F. 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