{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T19:53:18Z","timestamp":1776455598061,"version":"3.51.2"},"reference-count":182,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,28]],"date-time":"2025-06-28T00:00:00Z","timestamp":1751068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DOST","award":["MH CZ-DRO-VFN64165"],"award-info":[{"award-number":["MH CZ-DRO-VFN64165"]}]},{"name":"DOST","award":["FSE+ 2021\/2027 n. 2023\/3340"],"award-info":[{"award-number":["FSE+ 2021\/2027 n. 2023\/3340"]}]},{"name":"FIF","award":["MH CZ-DRO-VFN64165"],"award-info":[{"award-number":["MH CZ-DRO-VFN64165"]}]},{"name":"FIF","award":["FSE+ 2021\/2027 n. 2023\/3340"],"award-info":[{"award-number":["FSE+ 2021\/2027 n. 2023\/3340"]}]},{"name":"Czech Ministry of Health","award":["MH CZ-DRO-VFN64165"],"award-info":[{"award-number":["MH CZ-DRO-VFN64165"]}]},{"name":"Czech Ministry of Health","award":["FSE+ 2021\/2027 n. 2023\/3340"],"award-info":[{"award-number":["FSE+ 2021\/2027 n. 2023\/3340"]}]},{"name":"Fondo Sociale Europeo Plus","award":["MH CZ-DRO-VFN64165"],"award-info":[{"award-number":["MH CZ-DRO-VFN64165"]}]},{"name":"Fondo Sociale Europeo Plus","award":["FSE+ 2021\/2027 n. 2023\/3340"],"award-info":[{"award-number":["FSE+ 2021\/2027 n. 2023\/3340"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large variability of motor deficits on a beam-walking test. Histological and microscopic analyses confirmed worsening damage in the cerebellum (Cll; hypoplasia, increased death of neurons, and disrupted astroglial structures) and parietal motor cortex (hCtx; increased cell sufferance and astrogliosis). Clustering and network analyses of transcriptomic data reveal rearrangement of the physiological expression patterns and signaling pathways associated with bilirubin neurotoxicity. Bilirubin content among hyperbilirubinemic (jj) animals is overlapped, which suggests that the amount of bilirubin challenge does not fully explain the tissue, transcriptomic, proteomic, and neurobehavioral alterations. The expression of nine genes involved in key postnatal brain development processes is permanently altered in a phenotype-dependent manner. Among them, Grm1, a metabotropic glutamatergic receptor involved in glutamate neurotoxicity, is consistently downregulated in both brain regions both at the transcriptomic and proteomic levels. Our results support the role of Grm1 and glutamate as biomolecular markers of ongoing bilirubin neurotoxicity, suggesting the possibility to improve diagnosis by 1H-MR spectroscopy.<\/jats:p>","DOI":"10.3390\/ijms26136262","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T05:28:28Z","timestamp":1751347708000},"page":"6262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Transcriptomic and Proteomic Changes in the Brain Along with Increasing Phenotypic Severity in a Rat Model of Neonatal Hyperbilirubinemia"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3912-437X","authenticated-orcid":false,"given":"John Paul","family":"Llido","sequence":"first","affiliation":[{"name":"The Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, 34149 Basovizza, Italy"},{"name":"Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig City 1631, Philippines"},{"name":"Department of Life Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5505-2065","authenticated-orcid":false,"given":"Giorgia","family":"Valerio","sequence":"additional","affiliation":[{"name":"The Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, 34149 Basovizza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8643-4031","authenticated-orcid":false,"given":"David","family":"K\u0159epelka","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1285-6928","authenticated-orcid":false,"given":"Ale\u0161","family":"Dvo\u0159\u00e1k","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Bottin","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical, and Health Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrizio","family":"Zanconati","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical, and Health Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7323-0937","authenticated-orcid":false,"given":"Julia Theresa","family":"Regalado","sequence":"additional","affiliation":[{"name":"The Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, 34149 Basovizza, Italy"},{"name":"Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig City 1631, Philippines"},{"name":"Department of Life Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-7282","authenticated-orcid":false,"given":"Audrey","family":"Franceschi Biagioni","sequence":"additional","affiliation":[{"name":"Cognitive Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea, 265, 34136 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9965-8041","authenticated-orcid":false,"given":"Mohammed","family":"Qaisiya","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science, Hebron University, Hebron P785, Palestine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5318-0151","authenticated-orcid":false,"given":"Libor","family":"V\u00edtek","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic"},{"name":"4th Department of Internal Medicine, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, 12108 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"The Liver Brain Unit \u201cRita Moretti\u201d, Fondazione Italiana Fegato-Onlus, Bldg. 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