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Hypothermia increases cold-inducible protein expression and improves cerebellar-dependent learning after hypoxia ischemia in the neonatal rat

Pediatric Research volume 94, pages 539–546 (2023)Cite this article

Abstract

Background

Hypoxic ischemic encephalopathy remains a significant cause of developmental disability.1,2 The standard of care for term infants is hypothermia, which has multifactorial effects.3,4,5 Therapeutic hypothermia upregulates the cold-inducible protein RNA binding motif 3 (RBM3) that is highly expressed in developing and proliferative regions of the brain.6,7 The neuroprotective effects of RBM3 in adults are mediated by its ability to promote the translation of mRNAs such as reticulon 3 (RTN3).8

Methods

Hypoxia ischemia or control procedure was conducted in Sprague Dawley rat pups on postnatal day 10 (PND10). Pups were immediately assigned to normothermia or hypothermia at the end of the hypoxia. In adulthood, cerebellum-dependent learning was tested using the conditioned eyeblink reflex. The volume of the cerebellum and the magnitude of cerebral injury were measured. A second study quantified RBM3 and RTN3 protein levels in the cerebellum and hippocampus collected during hypothermia.

Results

Hypothermia reduced cerebral tissue loss and protected cerebellar volume. Hypothermia also improved learning of the conditioned eyeblink response. RBM3 and RTN3 protein expression were increased in the cerebellum and hippocampus of rat pups subjected to hypothermia on PND10.

Conclusions

Hypothermia was neuroprotective in male and female pups and reversed subtle changes in the cerebellum after hypoxic ischemic.

Impact

  • Hypoxic ischemic produced tissue loss and a learning deficit in the cerebellum.

  • Hypothermia reversed both the tissue loss and learning deficit.

  • Hypothermia increased cold-responsive protein expression in the cerebellum and hippocampus.

  • Our results confirm cerebellar volume loss contralateral to the carotid artery ligation and injured cerebral hemisphere, suggesting crossed-cerebellar diaschisis in this model.

  • Understanding the endogenous response to hypothermia might improve adjuvant interventions and expand the clinical utility of this intervention.

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Fig. 1: Hypoxia ischemia was conducted on postnatal day 10, and experimental endpoints are indicated.
Fig. 2: Eyeblink conditioning is consistently impaired in males and females when learning relies on the contralateral (Contra) cerebellar hemisphere and only impaired in a subset of males when reliant upon the ipsilateral (Ipsi) cerebellar hemisphere.
Fig. 3: Hypothermia prevented loss of volume in the contralateral cerebellum and reduced injury magnitude in the ipsilateral cerebrum.
Fig. 4: RBM3 and RTN3 protein levels are elevated in the cerebellum and hippocampus during the third hour of hypothermia.

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Data availability

The datasets generated and presented here are available from the corresponding author upon request.

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Funding

This study was supported by NIH/NICHD R03 HD085928 and NIH/NINDS R01 NS122777 to J.W., University of Maryland, Baltimore, Institute for Clinical & Translational Science Award to J.W., and the Richard Schwartz Research Award to A.B.

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  1. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA

    Miguel Perez-Pouchoulen

  2. Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA

    Ayodele Jaiyesimi, Keti Bardhi, Jaylyn Waddell & Aditi Banerjee

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M.P.-P. made substantial contributions to data collection and revising the manuscript critically for important intellectual content and final approval of the version to be submitted. A.J. made substantial contributions to data collection and organization. K.B. made substantial contributions to data collection and organization. J.W. made substantial contributions to conception and design, gathering, analyzing and interpreting data, drafting and revising the article critically for important intellectual content, and final approval of the version to be submitted. A.B. made substantial contributions to conception and design, acquisition of data and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be submitted.

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Correspondence to Jaylyn Waddell.

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Perez-Pouchoulen, M., Jaiyesimi, A., Bardhi, K. et al. Hypothermia increases cold-inducible protein expression and improves cerebellar-dependent learning after hypoxia ischemia in the neonatal rat. Pediatr Res 94, 539–546 (2023). https://doi.org/10.1038/s41390-023-02535-z

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