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Updated: Oct 22, 2025
Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
Temporal brain microRNA expression changes in a mouse model of neonatal hypoxic-ischemic injury
Eric S Peeples1, Namood-E Sahar2, William Snyder2
1Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA. epeeples@childrensomaha.org.
Background:
Neonatal hypoxic-ischemic brain injury (HIBI) results in significant morbidity and mortality despite current standard therapies. MicroRNAs (miRNAs) are a promising therapeutic target; however, there is a paucity of data on endogenous miRNA expression of the brain after HIBI during the primary therapeutic window (6-72 h after injury).
Methods:
Postnatal day 9 mouse pups underwent unilateral carotid ligation+hypoxia (HIBI), sham surgery+hypoxia, or sham surgery+normoxia (controls). miRNA sequencing was performed on the ipsilateral brain of each of the three groups plus the contralateral HIBI brain at 24 and 72 h after injury. Findings were validated in eight key miRNAs by quantitative polymerase chain reaction.
Results:
Hypoxia resulted in significant differential expression of 38 miRNAs at both time points. Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI at 24 and 72 h, with 3 of the 4 demonstrating multiphasic expression (different direction of differential expression at 24 versus 72 h).
Conclusions:
Our global assessment of subacute changes in brain miRNA expression after hypoxia or HIBI will advance research into targeted miRNA-based interventions. It will be important to consider the multiphasic miRNA expression patterns after HIBI to identify optimal timing for individual interventions.
Impact:
This study is the first to comprehensively define endogenous brain microRNA expression changes outside of the first hours after neonatal hypoxic-ischemic brain injury (HIBI). Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI and therefore deserve further investigation as possible therapeutic targets. The expression profiles described will support the design of future studies attempting to develop miRNA-based interventions for infants with HIBI. At 24 h after injury, contralateral HIBI miRNA expression patterns were more similar to ipsilateral HIBI than to controls, suggesting that the contralateral brain is not an appropriate "internal control" for miRNA studies in this model.
Insights
Neonatal hypoxic-ischemic brain injury (HIBI) alters brain microRNA (miRNA) expression. Specific miRNAs like Mir-2137, -335, -137, and -376c show significant changes, offering potential therapeutic targets for HIBI.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neonatal hypoxic-ischemic brain injury (HIBI) is a major cause of infant mortality and morbidity.
- Current therapies for HIBI are limited, highlighting the need for novel therapeutic strategies.
- MicroRNAs (miRNAs) are implicated in HIBI, but their expression patterns during the subacute phase (6-72 hours post-injury) are not well understood.
Purpose of the Study:
- To comprehensively define endogenous brain miRNA expression changes in the subacute phase following neonatal HIBI.
- To identify specific miRNAs that are differentially expressed after HIBI and could serve as therapeutic targets.
- To investigate the temporal dynamics of miRNA expression changes in response to HIBI.
Main Methods:
- Neonatal mouse pups (postnatal day 9) were subjected to unilateral carotid ligation and hypoxia (HIBI), sham surgery with hypoxia, or sham surgery with normoxia (controls).
- miRNA sequencing was performed on ipsilateral and contralateral brain tissues at 24 and 72 hours post-injury.
- Quantitative polymerase chain reaction (qPCR) was used to validate the expression levels of key differentially expressed miRNAs.
Main Results:
- Significant differential expression of 38 miRNAs was observed at both 24 and 72 hours after HIBI.
- Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI at both time points.
- Three of these four miRNAs exhibited multiphasic expression patterns, with differential expression in opposite directions at 24 versus 72 hours post-injury.
Conclusions:
- This study provides the first comprehensive analysis of subacute brain miRNA expression changes following neonatal HIBI.
- The identified miRNAs (Mir-2137, -335, -137, and -376c) represent promising candidates for targeted miRNA-based therapeutic interventions.
- Understanding the multiphasic nature of miRNA expression is crucial for optimizing the timing of future HIBI interventions.
