Behavioral and neuroanatomical outcomes following altered serotonin expression in a hypoxic-ischemic injury neonate rodent model
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Updated: Dec 1, 2025
Neurobehavioral Assessments in a Mouse Model of Neonatal Hypoxic-ischemic Brain Injury
Published on: November 24, 2017
S G Casavant1, H Li2, X Cong1
1University of Connecticut, School of Nursing, Storrs, CT, USA.
Insights
Selective serotonin reuptake inhibitors (SSRIs) did not increase anxiety in preterm rodent models but showed potential neuroprotection and improved cognition following hypoxic-ischemic injury, suggesting novel therapeutic avenues.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Premature birth (<37 weeks) increases risks for adverse medical and neurological outcomes.
- Neonatal intensive care unit (NICU) stress can alter SLC6A4 gene methylation, impacting serotonin transport and increasing risks for anxiety, depression, and autism spectrum disorders.
- Altered serotonin signaling is implicated in neurodevelopmental trajectories and behavioral outcomes.
Purpose of the Study:
- To investigate the impact of altered serotonin levels on behavioral and neuroanatomical development in a neonatal rodent model.
- To examine the effects of hypoxic-ischemic (HI) injury and selective serotonin reuptake inhibitor (SSRI) treatment on neurodevelopmental outcomes.
Main Methods:
- Wistar rat pups were subjected to either hypoxic-ischemic (HI) injury or a sham procedure.
- Pups received chronic SSRI (Citalopram HBr) or saline (NS) treatment to model SLC6A4 methylation effects.
- Behavioral assessments and neuropathological evaluations were performed.
Main Results:
- Hypoxic-ischemic injury impaired performance on behavioral tasks.
- SSRI treatment alone did not significantly increase anxiety levels.
- Subjects with both HI injury and SSRI treatment demonstrated faster learning compared to HI-injured subjects receiving saline.
- Histological analysis revealed larger brain volumes in SSRI-treated subjects compared to saline-treated controls.
Conclusions:
- SSRI treatment in non-injured subjects mirrored SLC6A4 methylation effects, showing increased anxiety patterns.
- A paradoxical trend of improved cognition was observed in HI+SSRI subjects versus HI+NS subjects.
- These findings suggest a potential neuroprotective role for SSRIs in the context of hypoxic-ischemic injury, possibly mediated by serotonin-induced neurogenesis.
Background:
Children born prematurely (<37 gestational weeks) are at risk for a variety of adverse medical events. They may experience ischemic and/or hemorrhagic events leading to negative neural sequelae. They are also exposed to repeated stressful experiences as part of life-saving care within the neonatal intensive care unit (NICU). These experiences have been associated with methylation of SLC6A4, a gene which codes for serotonin transport proteins, and is associated with anxiety, depression, and increased incidence of autism spectrum disorders.The purpose of this study was to examine the effects of altered serotonin levels on behavioral and neuroanatomical outcomes in a neonatal rodent model with or without exposure to hypoxic-ischemic (HI) injury.
Methods:
Wistar rat pups were randomly assigned to either HI injury or sham groups. Pups within each group were treated with a chronic SSRI (Citalopram HBr) to simulate the effects of SLC6A4 methylation, or saline (NS). Subjects were assessed on behavioral tasks and neuropathologic indices.
Results:
HI injured subjects performed poorly on behavioral tasks. SSRI subjects did not display significantly greater anxiety. HI + SSRI subjects learned faster than HI+NS. Histologically, SSRI subjects had predominantly larger brain volumes than NS.
Conclusion:
SSRI treated subjects without injury showed patterns of increased anxiety, consistent with theories of SLC6A4 methylation. The paradoxical trend to improved cognition in HI+SSRI subjects relative to HI alone, may reflect an unexpected SSRI neuroprotective effect in the presence of injury, and may be related to serotonin-induced neurogenesis.
