Neonatal hyperbilirubinemia differentially alters the neurochemical profiles of the developing cerebellum and hippocampus in a preterm Gunn rat model

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Neonatal hyperbilirubinemia (NHB) can lead to brain injury in newborn infants by affecting specific regions including the cerebellum and hippocampus. Extremely preterm infants are more vulnerable to bilirubin neurotoxicity, but the mechanism and extent of injury is not well understood. A preterm version of the Gunn rat model was utilized to investigate severe preterm NHB. Homozygous/jaundiced Gunn rat pups were injected (i.p.) on postnatal day (P) 5 with sulfadimethoxine, which increases serum free bilirubin capable of crossing the blood–brain barrier and causing brain injury. The neurochemical profiles of the cerebellum and hippocampus were determined using in vivo 1H MRS at 9.4 T on P30 and compared with those of heterozygous/non-jaundiced control rats. Transcript expression of related genes was determined by real-time quantitative PCR. MRI revealed significant morphological changes in the cerebellum of jaundiced rats. The concentrations of myo-inositol (+54%), glucose (+51%), N-acetylaspartylglutamate (+21%), and the sum of glycerophosphocholine and phosphocholine (+17%) were significantly higher in the cerebellum of the jaundiced group compared with the control group. Despite the lack of morphologic changes in the hippocampus, the concentration of myo-inositol (+9%) was higher and the concentrations of creatine (−8%) and of total creatine (−3%) were lower in the jaundiced group. In the hippocampus, expression of calcium/calmodulin dependent protein kinase II alpha (Camk2a), glucose transporter 1 (Glut1), and Glut3 transcripts were downregulated in the jaundiced group. In the cerebellum, glial fibrillary acidic protein (Gfap), myelin basic protein (Mbp), and Glut1 transcript expression was upregulated in the jaundiced group. These results indicate osmotic imbalance, gliosis, and changes in energy utilization and myelination, and demonstrate that preterm NHB critically affects brain development in a region-specific manner, with the cerebellum more severely impacted than the hippocampus.

Original languageEnglish (US)
JournalNMR in biomedicine
StateAccepted/In press - 2023

Bibliographical note

Funding Information:
The authors would like to acknowledge the following contributions to this study: a Progressive Grant from the Department of Pediatrics to KMS; the Center for Magnetic Resonance Research at the University of Minnesota (supported by the W.M. Keck Foundation and National Institutes of Health grants P41 EB027061 and P30 NS076408); the Rat Resource and Research Center (Gunn rat purchase, supported by funding from the NIH P40 OD011062); and Garima Singh, Kathleen Czerniak, Mandkhai Molomjamts, and Brita Larsen (laboratory technician support).

Publisher Copyright:
© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.


  • Gunn rat
  • MRS
  • cerebellum
  • hippocampus
  • hyperbilirubinemia
  • neurochemical profile
  • preterm infant

PubMed: MeSH publication types

  • Journal Article


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